Updated on 2021/12/02

写真a

 
Honda Tomoyuki
 
Organization
Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
External link

Degree

  • 博士(医学) ( 大阪大学 )

Research Interests

  • 医化学一般

  • ウイルス学

  • psychiatric disorders

  • 病態医化学

  • virus infection

Research Areas

  • Life Science / Medical biochemistry

  • Life Science / Pathological biochemistry

  • Life Science / Virology

Education

  • Osaka University   医学系研究科  

    - 2004

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    Country: Japan

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  • Osaka University    

    - 1999

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  • Osaka University   医学部   医

    - 1999

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    Country: Japan

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Research History

  • Osaka University   Graduate School of Medicine Center for Twin Research

    2021.1

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  • Okayama University   Graduate School of Medicine , Dentistry and Pharmaceutical Sciences   Professor

    2021.1

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  • Osaka University   Graduate School of Medicine, Center for Twin Research

    2016.10 - 2021.12

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  • Osaka University   Graduate School of Medicine   Associate Professor

    2016.4 - 2020.12

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  • Kyoto University   ウイルス研究所   Assistant Professor

    2011.10 - 2016.3

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  • The University of Tokyo The Institute of Medical Science, Laboratory Animal Research Center   Assistant Professor

    2010.2 - 2011.9

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Professional Memberships

Committee Memberships

  • 大阪大学医学研究科   病原体等安全管理委員会  

    2018.10   

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  • 大阪大学   研究倫理審査委員会  

    2018.4   

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  • 大阪大学医学部附属病院   感染対策委員会  

    2018.4   

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  • 大阪大学医学部附属病院   ICTラウンド  

    2016.11   

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    Committee type:Other

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Papers

  • A patient with human coronavirus NL63 falsely diagnosed with COVID-19; Lesson learned for the importance of definitive diagnosis Reviewed

    Yuki Otsuka, Hideharu Hagiya, Yasuhiro Nakano, Daisuke Omura, Kou Hasegawa, Haruto Yamada, Koji Iio, Tomoyuki Honda, Fumio Otsuka

    Journal of Infection and Chemotherapy   27 ( 7 )   1126 - 1128   2021.7

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.jiac.2021.05.001

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  • A Human Endogenous Bornavirus-Like Nucleoprotein Encodes a Mitochondrial Protein Associated with Cell Viability

    Kan Fujino, Masayuki Horie, Shohei Kojima, Sae Shimizu, Aya Nabekura, Hiroko Kobayashi, Akiko Makino, Tomoyuki Honda, Keizo Tomonaga

    Journal of Virology   95 ( 14 )   2021.6

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    Publishing type:Research paper (scientific journal)   Publisher:American Society for Microbiology  

    Our genomes contain molecular fossils of ancient viruses, called endogenous virus elements (EVEs). Mounting evidence suggests that EVEs derived from nonretroviral RNA viruses have acquired functions in host cells during evolution.

    DOI: 10.1128/jvi.02030-20

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  • Characterization of an active LINE-1 in the naked mole-rat genome. International journal

    Shunichi Yamaguchi, Shizuka Nohara, Yuki Nishikawa, Yusuke Suzuki, Yoshimi Kawamura, Kyoko Miura, Keizo Tomonaga, Keiji Ueda, Tomoyuki Honda

    Scientific reports   11 ( 1 )   5725 - 5725   2021.3

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    Naked mole-rats (NMRs, Heterocephalus glaber) are the longest-living rodent species. A reason for their long lifespan is pronounced cancer resistance. Therefore, researchers believe that NMRs have unknown secrets of cancer resistance and seek to find them. Here, to reveal the secrets, we noticed a retrotransposon, long interspersed nuclear element 1 (L1). L1s can amplify themselves and are considered endogenous oncogenic mutagens. Since the NMR genome contains fewer L1-derived sequences than other mammalian genomes, we reasoned that the retrotransposition activity of L1s in the NMR genome is lower than those in other mammalian genomes. In this study, we successfully cloned an intact L1 from the NMR genome and named it NMR-L1. An L1 retrotransposition assay using the NMR-L1 reporter revealed that NMR-L1 was active retrotransposon, but its activity was lower than that of human and mouse L1s. Despite lower retrotrasposition activity, NMR-L1 was still capable of inducing cell senescence, a tumor-protective system. NMR-L1 required the 3' untranslated region (UTR) for retrotransposition, suggesting that NMR-L1 is a stringent-type of L1. We also confirmed the 5' UTR promoter activity of NMR-L1. Finally, we identified the G-quadruplex structure of the 3' UTR, which modulated the retrotransposition activity of NMR-L1. Taken together, the data indicate that NMR-L1 retrotranspose less efficiently, which may contribute to the cancer resistance of NMRs.

    DOI: 10.1038/s41598-021-84962-8

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  • Radioligand Assay-Based Detection of Antibodies against SARS-CoV-2 in Hospital Workers Treating Patients with Severe COVID-19 in Japan. International journal

    Hidenori Matsunaga, Akiko Makino, Yasuhiro Kato, Teruaki Murakami, Yuta Yamaguchi, Atsushi Kumanogoh, Yuichiro Oba, Satoshi Fujimi, Tomoyuki Honda, Keizo Tomonaga

    Viruses   13 ( 2 )   2021.2

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    This study aimed to clarify whether infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is prevalent among the staff of a hospital providing treatment to patients with severe coronavirus disease 2019 (COVID-19) using radioligand assay (RLA). One thousand samples from the staff of a general hospital providing treatment to patients with severe COVID-19 were assayed for SARS-CoV-2 nucleocapsid protein (N) IgG using RLA. Nine patients with COVID-19 who had been treated in inpatient settings and had already recovered were used as control subjects, and 186 blood donor samples obtained more than 10 years ago were used as negative controls. Four of the 1000 samples showed apparently positive results, and approximately 10 or more samples showed slightly high counts. Interestingly, a few among the blood donor samples also showed slightly high values. To validate the results, antibody examinations using ELISA and neutralizing antibody tests were performed on 21 samples, and chemiluminescence immunoassay (CLIA) was performed on 201 samples, both resulting in a very high correlation. One blood donor sample showed slightly positive results in both RLA and CLIA, suggesting a cross-reaction. This study showed that five months after the pandemic began in Japan, the staff of a general hospital with a tertiary emergency medical facility had an extremely low seroprevalence of the antibodies against SARS-CoV-2. Further investigation will be needed to determine whether the slightly high results were due to cross-reactions or a low titer of anti-SARS-CoV-2 antibodies. The quantitative RLA was considered sensitive enough to detect low titers of antibodies.

    DOI: 10.3390/v13020347

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  • Effects of activation of the LINE‐1 antisense promoter on the growth of cultured cells Reviewed

    Tomoyuki Honda, Yuki Nishikawa, Kensuke Nishimura, Da Teng, Keiko Takemoto, Keiji Ueda

    Scientific Reports   10 ( 1 )   in press   2020.12

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Springer Science and Business Media LLC  

    <title>Abstract</title>Long interspersed element 1 (LINE-1, or L1) is a retrotransposon that constitutes ~ 17% of the human genome. Although ~ 6000 full-length L1s spread throughout the human genome, their biological significance remains undetermined. The L1 5′ untranslated region has bidirectional promoter activity with a sense promoter driving L1 mRNA production and an antisense promoter (ASP) driving the production of L1-gene chimeric RNAs. Here, we stimulated L1 ASP activity using CRISPR-Cas9 technology to evaluate its biological impacts. Activation of the L1 ASP upregulated the expression of L1 ASP-driven ORF0 and enhanced cell growth. Furthermore, the exogenous expression of ORF0 also enhanced cell growth. These results indicate that activation of L1 ASP activity fuels cell growth at least through ORF0 expression. To our knowledge, this is the first report demonstrating the role of the L1 ASP in a biological context. Considering that L1 sequences are desilenced in various tumor cells, our results indicate that activation of the L1 ASP may be a cause of tumor growth; therefore, interfering with L1 ASP activity may be a potential strategy to suppress the growth.

    DOI: 10.1038/s41598-020-79197-y

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    Other Link: http://www.nature.com/articles/s41598-020-79197-y

  • A traditional Chinese medicine, maoto, suppresses hepatitis B virus production Reviewed

    Md Arifur Rahman, Keiji Ueda, Tomoyuki Honda

    Frontiers in Cellular and Infection Microbiology   in press   2020.12

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

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  • Modeling Borna Disease Virus In Vitro Spread Reveals the Mode of Antiviral Effect Conferred by an Endogenous Bornavirus-Like Element Reviewed International journal

    Kwang Su Kim, Yusuke Yamamoto, Shinji Nakaoka, Keizo Tomonaga, Shingo Iwami, Tomoyuki Honda

    Journal of Virology   94 ( 21 )   e01204-20   2020.8

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Society for Microbiology  

    <title>ABSTRACT</title>
    Endogenous retroviruses have demonstrated exaptation during long-term evolution with hosts, e.g., resulting in acquisition of antiviral effect on related extant viral infections. While empirical studies have found that an endogenous bornavirus-like element derived from viral nucleoprotein (itEBLN) in the ground squirrel genome shows antiviral effect on virus replication and <italic>de novo</italic> infection, the antiviral mechanism, dynamics, and quantitative effect of itEBLN remain unknown. In this study, we experimentally and theoretically investigated the dynamics of how an extant bornavirus, Borna disease virus 1 (BoDV-1), spreads and replicates in uninfected, BoDV-1-infected, and itEBLN-expressing cultured cells. Quantifying antiviral effect based on time course data sets, we found that the antiviral effects of itEBLN are estimated to be 75% and 34% on intercellular virus spread and intracellular virus replication, respectively. This discrepancy between intercellular virus spread and intracellular viral replication suggests that viral processes other than the replication of viral ribonucleoprotein complex (RNP) contributed to the suppression of virus spread in itEBLN-expressing cells. Because itEBLN binds to the BoDV-1 RNP, the suppression of viral RNP trafficking can be an attractive candidate explaining this discrepancy.


    <bold>IMPORTANCE</bold> Accumulating evidence suggests that some endogenous viral elements (EVEs), including endogenous retroviruses and endogenous nonretroviral virus elements, have acquired functions in the host as a result of long-term coevolution. Recently, an endogenous bornavirus-like element (itEBLN) found in the ground squirrel genome has been shown to have antiviral activity against exogenous bornavirus infection. In this study, we first quantified bornavirus spread in cultured cells and then calculated the antiviral activity of itEBLN on bornavirus infection. The calculated antiviral activity of itEBLN suggests its suppression of multiple processes in the viral life cycle. To our knowledge, this is the first study quantifying the antiviral activity of EVEs and speculating on a model of how some EVEs have acquired antiviral activity during host-virus arms races.

    DOI: 10.1128/jvi.01204-20

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  • Complete Genome Sequence of a Precore-Defective Hepatitis B Virus Genotype D2 Strain Isolated in Bangladesh. Reviewed International journal

    Md Golzar Hossain, Md Muket Mahmud, Md Arifur Rahman, Sharmin Akter, K H M Nazmul Hussain Nazir, Sukumar Saha, Masami Wada, Eriko Ohsaki, Tomoyuki Honda, Keiji Ueda

    Microbiology resource announcements   9 ( 11 )   2020.3

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    Hepatitis B virus (HBV) genomic mutations affect viral replication, disease progression, and diagnostic and vaccination efficiency. There is limited information regarding characterization and mutational analysis of HBV isolated in Bangladesh. Here, we report the complete nucleotide sequence of a precore-defective HBV genotype D2 strain isolated in Bangladesh.

    DOI: 10.1128/MRA.00083-20

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  • Kaposi's sarcoma-associated herpesvirus is cell-intrinsically controlled in latency in microgravity. Reviewed International journal

    Tomoyuki Honda, Ryota Nakayama, Yumi Kawahara, Louis Yuge, Keiji Ueda

    Virus research   276   197821 - 197821   2020.1

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    In the next several decades, humans will explore deep space, including Mars. During long-term space flight, astronauts will be exposed to various physical stressors. Among these stressors, microgravity may compromise the immune system. Consistently, the reactivation of several latent herpesviruses has been reported in astronauts. Although herpesvirus infection status is determined by both cell-intrinsic and -extrinsic factors, it remains unclear which factors play major roles in the virus reactivation in microgravity. Here, using Kaposi's sarcoma-associated herpesvirus (KSHV)-infected cells, we found that KSHV is cell-intrinsically controlled in latency in microgravity. Innate immunity appeared to be unaffected in microgravity, while the expression of some restriction factors against KSHV, such as CTCF and AMPK, was upregulated. Collectively, the infected cells in microgravity can control KSHV in latency, possibly by unimpaired innate immunity and upregulated KSHV restriction factors. This is the first pilot study of the conflicts between cell-intrinsic defense systems and viruses in microgravity and provides fundamental information regarding host-virus interactions in microgravity.

    DOI: 10.1016/j.virusres.2019.197821

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  • Relaunching human bornavirus research from severe encephalitis cases with unclear etiology Invited Reviewed

    HONDA Tomoyuki

    The Lancet Infectious Diseases   in press   2020.1

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  • RNA Virus-Based Episomal Vector with a Fail-Safe Switch Facilitating Efficient Genetic Modification and Differentiation of iPSCs. Reviewed International journal

    Yumiko Komatsu, Dan Takeuchi, Tomoya Tokunaga, Hidetoshi Sakurai, Akiko Makino, Tomoyuki Honda, Yasuhiro Ikeda, Keizo Tomonaga

    Molecular therapy. Methods & clinical development   14   47 - 55   2019.9

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    A gene delivery system that allows efficient and safe stem cell modification is critical for next-generation stem cell therapies. An RNA virus-based episomal vector (REVec) is a gene transfer system developed based on Borna disease virus (BoDV), which facilitates persistent intranuclear RNA transgene delivery without integrating into the host genome. In this study, we analyzed susceptibility of human induced pluripotent stem cell (iPSC) lines from different somatic cell sources to REVec, along with commonly used viral vectors, and demonstrated highly efficient REVec transduction of iPSCs. Using REVec encoding myogenic transcription factor MyoD1, we further demonstrated potential application of the REVec system for inducing differentiation of iPSCs into skeletal muscle cells. Of note, treatment with a small molecule, T-705, completely eliminated REVec in persistently transduced cells. Thus, the REVec system offers a versatile toolbox for stable, integration-free iPSC modification and trans-differentiation, with a unique switch-off mechanism.

    DOI: 10.1016/j.omtm.2019.05.010

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  • Identification of a Retroelement-Containing Human Transcript Induced in the Nucleus by Vaccination. Reviewed International journal

    Tomoyuki Honda, Keiko Takemoto, Keiji Ueda

    International journal of molecular sciences   20 ( 12 )   2875   2019.6

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    Endogenous retroelements constitute almost half of the mammalian genome. Given that more than 60% of human genomic bases are transcribed, transcripts containing these retroelements may impact various biological processes. However, the physiological roles of most retroelement-containing transcripts are yet to be revealed. Here, we profiled the expression of retroelement-containing human transcripts during vaccination and found that vaccination upregulated transcripts containing only particular retroelements, such as the MLT-int element of endogenous retroviruses. MLT-int-containing transcripts were distributed mainly in the nucleus, suggesting their unique roles in the nucleus. Furthermore, we demonstrated that MLT-int RNA suppressed interferon promoter activity in the absence of immune stimuli. Based on these lines of evidence, we speculate a model of a role of the previously unnoticed MLT-int element in preventing excess innate immune activation after elimination of immune stimuli. Our results may emphasize the importance of retroelement-containing transcripts in maintaining host immune homeostasis.

    DOI: 10.3390/ijms20122875

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  • Latent infection with Kaposi's sarcoma-associated herpesvirus enhances retrotransposition of long interspersed element-1. Reviewed International journal

    Ryota Nakayama, Yumiko Ueno, Keiji Ueda, Tomoyuki Honda

    Oncogene   38 ( 22 )   4340 - 4351   2019.5

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    Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), a gamma-2 herpesvirus, is the causative agent of KS, primary effusion lymphoma (PEL), and a plasma cell variant of multicentric Castleman's disease. Although KSHV latency is detected in KS-related tumors, oncogenic pathways activated by KSHV latent infection are not fully understood. Here, we found that retrotransposition of long interspersed element-1 (L1), a retrotransposon in the human genome, was enhanced in PEL cells. Among the KSHV latent genes, viral FLICE-inhibitory protein (vFLIP) enhanced L1 retrotransposition in an NF-κB-dependent manner. Intracellular cell adhesion molecule-1 (ICAM-1), an NF-κB target, regulated the vFLIP-mediated enhancement of L1 retrotransposition. Furthermore, ICAM-1 downregulated the expression of Moloney leukemia virus 10 (MOV10), an L1 restriction factor. Knockdown of ICAM-1 or overexpression of MOV10 relieved the vFLIP-mediated enhancement of L1 retrotransposition. Collectively, during KSHV latency, vFLIP upregulates ICAM-1 in an NF-κB-dependent manner, which, in turn, downregulates MOV10 expression and thereby enhances L1 retrotransposition. Because active L1 retrotransposition can lead to genomic instability, which is commonly found in KS and PEL, activation of L1 retrotransposition during KSHV latency may accelerate oncogenic processes through enhancing genomic instability. Our results suggest that L1 retrotransposition may be a novel target for impeding tumor development in KSHV-infected patients.

    DOI: 10.1038/s41388-019-0726-5

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  • Profiling of LINE-1-Related Genes in Hepatocellular Carcinoma. Invited Reviewed

    Honda T, Rahman MA

    International Journal of Molecular Sciences   20 ( 3 )   645   2019.2

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    DOI: 10.3390/ijms20030645

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  • A Small Interfering RNA Cocktail Targeting the Nucleoprotein and Large Protein Genes Suppresses Borna Disease Virus Infection. Reviewed International journal

    Da Teng, Shunsuke Obika, Keiji Ueda, Tomoyuki Honda

    Frontiers in microbiology   10   2781 - 2781   2019

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    Recently, Borna disease virus (BoDV-1)-related fatal encephalitis human cases have been reported, which highlights the potential of BoDV-1 to cause fatal human diseases. To protect the infected brain from lethal damage, it is critical to control BoDV-1 as quickly as possible. At present, antivirals against BoDV-1 are limited, and therefore, novel types of antivirals are needed. Here, we developed a novel treatment using small interfering RNAs (siRNAs) against BoDV-1. We screened several siRNAs targeting the viral N, M, and L genes for BoDV-1-reducing activity. Among the screened candidates, we chose two siRNAs that efficiently decreased the BoDV-1 load in persistently BoDV-1-infected cells to prepare a siRNA cocktail (TD-Borna) for BoDV-1 treatment. TD-Borna successfully reduced the BoDV-1 load without enhancing the risk of emergence of escape mutants. The combination of TD-Borna and T-705, a previously reported antiviral agent against bornaviruses, decreased the BoDV-1 load more efficiently than TD-Borna or T-705 alone. Furthermore, TD-Borna efficiently decreased the BoDV-1 load in BoDV-1-infected neuron-derived cells, in which T-705 did not decrease the viral load. Overall, we developed a novel antiviral candidate against BoDV-1, TD-Borna, that can be used in combination with T-705 and is effective against BoDV-1 in neuron-derived cells, in which T-705 is less effective. Considering that BoDV-1 is highly neurotropic, TD-Borna can offer a promising option to improve the outcome of BoDV-1 infection.

    DOI: 10.3389/fmicb.2019.02781

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  • Development of an RNA Virus-Based Episomal Vector Capable of Switching Transgene Expression. Reviewed International journal

    Yusuke Yamamoto, Keizo Tomonaga, Tomoyuki Honda

    Frontiers in microbiology   10   2485 - 2485   2019

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    Viral vectors are efficient gene delivery systems, although most of these vectors still present limitations to their practical use, such as achieving only transient transgene expression and a risk of insertional mutations. We have recently developed an RNA virus-based episomal vector (REVec), based on nuclear-replicating Borna disease virus (BoDV). REVec can transduce transgenes into various types of cells and stably express transgenes; however, an obstacle to the practical use of REVec is the lack of a mechanism to turn off transgene expression once REVec is transduced. Here, we developed a novel REVec system, REVec-L2b9, in which transgene expression can be switched on and off by using a theophylline-dependent self-cleaving riboswitch. Transgene expression from REVec-L2b9 was suppressed in the absence of theophylline and induced by theophylline administration. Conversely, transgene expression from REVec-L2b9 was switched off by removing theophylline. To our knowledge, REVec-L2b9 is the first nuclear-replicating RNA virus vector capable of switching transgene expression on and off as needed, which will expand the potential for gene therapies by increasing safety and usability.

    DOI: 10.3389/fmicb.2019.02485

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  • Inhibition of LINE-1 Retrotransposition by Capsaicin. Reviewed International journal

    Yuki Nishikawa, Ryota Nakayama, Shunsuke Obika, Eriko Ohsaki, Keiji Ueda, Tomoyuki Honda

    International journal of molecular sciences   19 ( 10 )   2018.10

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    Long interspersed nuclear element 1 (LINE-1 or L1) is a non-long terminal repeat (LTR) retrotransposon that constitutes approximately 17% of the human genome. Since approximately 100 copies are still competent for retrotransposition to other genomic loci, dysregulated retrotransposition of L1 is considered to be a major risk factor of endogenous mutagenesis in humans. Thus, it is important to find drugs to regulate this process. Although various chemicals are reportedly capable of affecting L1 retrotransposition, it is poorly understood whether phytochemicals modulate L1 retrotransposition. Here, we screened a library of compounds that were derived from phytochemicals for reverse transcriptase (RT) inhibition with an in vitro RT assay. We identified capsaicin as a novel RT inhibitor that also suppressed L1 retrotransposition. The inhibitory effect of capsaicin on L1 retrotransposition was mediated neither through its receptor, nor through its modulation of the L1 promoter and/or antisense promoter activity, excluding the possibility that capsaicin indirectly affected L1 retrotransposition. Collectively, capsaicin suppressed L1 retrotransposition most likely by inhibiting the RT activity of L1 ORF2p, which is the L1-encoded RT responsible for L1 retrotransposition. Given that L1-mediated mutagenesis can cause tumorigenesis, our findings suggest the potential of capsaicin for suppressing cancer development.

    DOI: 10.3390/ijms19103243

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  • Two Neuropsychiatric Cases Seropositive for Bornavirus Improved by Ribavirin Reviewed

    Hidenori Matsunaga, Akio Fukumori, Kohji Mori, Tomoyuki Honda, Takeshi Uema, Keizo Tomonaga

    Japanese Journal of Infectious Diseases   71 ( 5 )   338 - 342   2018.9

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    Publishing type:Research paper (scientific journal)   Publisher:Editorial Committee of Japanese Journal of Infectious Diseases, National Institute of Infectious Dis  

    DOI: 10.7883/yoken.jjid.2017.585

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  • vFLIP upregulates IKKε, leading to spindle morphology formation through RelA activation. Reviewed International journal

    Zunlin Yang, Tomoyuki Honda, Keiji Ueda

    Virology   522   106 - 121   2018.9

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    Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) vFLIP, a latent gene of KSHV, was first identified as a FLICE-inhibitory protein (FLIP) protecting cells from apoptosis. The vFLIP protein has been shown to activate the NF-κB signaling involved in spindle morphology formation both in HUVECs infected with KSHV and Kaposi's sarcoma (KS) itself. In this study, we independently established stably vFLIP-expressing cells and showed that they exhibited upregulated NF-κB family protein expression independent of the ability of IKKs to bind vFLIP. Further, vFLIP induced upregulation of IKKε, phosphorylation of RelA at Ser468 (p-RelA S468) and nuclear localization of Re1A concomitant with spindle morphology formation, and these effects were reversed by knockdown of IKKε and treatment with Bay-11. Overexpression of IKKε alone also showed spindle morphology formation with p-RelA S468. In conclusion, the spindle cell morphology in KS should be induced by RelA activation (p-RelA S468) by IKKε upregulation in vFLIP-expressing EA hy926 cells.

    DOI: 10.1016/j.virol.2018.07.007

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  • Prevalence of antibodies against Borna disease virus proteins in Japanese children with autism spectrum disorder. Reviewed International journal

    Tomoyuki Honda, Kozue Sofuku, Hidenori Matsunaga, Masaya Tachibana, Ikuko Mohri, Masako Taniike, Keizo Tomonaga

    Microbiology and immunology   2018.5

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    Bornavirus infection is observed in both animals, including humans. However, bornavirus epidemiology in humans, especially in children, remains unclear. Here, we evaluated antibodies against bornaviruses in Japanese children with autism spectrum disorder (ASD) using immunofluorescence analysis, western blotting, and radio ligand assay. The prevalence of antibodies against bornavirus-specific speckles, N, and P proteins were 22%, 48%, and 33%, respectively, in the ASD children. According to our criteria, the prevalence of antibodies against bornaviruses was 7.4% in the ASD children. This is the first report of the serological prevalence of bornavirus in Japanese children. Our results provide valuable baseline-data regarding bornavirus epidemiology in children for future studies.

    DOI: 10.1111/1348-0421.12603

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  • A single amino acid substitution within the paramyxovirus Sendai virus nucleoprotein is a critical determinant for production of interferon-beta-inducing copyback-type defective interfering genomes Reviewed

    Asuka Yoshida, Ryoko Kawabata, Tomoyuki Honda, Kouji Sakai, Yasushi Ami, Takemasa Sakaguchi, Takashi Irie

    Journal of Virology   92 ( 5 )   2018.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Society for Microbiology  

    One of the first defenses against infecting pathogens is the innate immune system activated by cellular recognition of pathogen-associated molecular patterns (PAMPs). Although virus-derived RNA species, especially copyback (cb)-type defective interfering (DI) genomes, have been shown to serve as real PAMPs, which strongly induce interferon-beta (IFN-β) during mononegavirus infection, the mechanisms underlying DI generation remain unclear. Here, for the first time, we identified a single amino acid substitution causing production of cbDI genomes by successful isolation of two distinct types of viral clones with cbDI-producing and cbDI-nonproducing phenotypes from the stock Sendai virus (SeV) strain Cantell, which has been widely used in a number of studies on antiviral innate immunity as a representative IFN-β-inducing virus. IFN-β induction was totally dependent on the presence of a significant amount of cbDI genomecontaining viral particles (DI particles) in the viral stock, but not on deficiency of the IFNantagonistic viral accessory proteins C and V. Comparison of the isolates indicated that a single amino acid substitution found within the N protein of the cbDI-producing clone was enough to cause the emergence of DI genomes. The mutated N protein of the cbDI-producing clone resulted in a lower density of nucleocapsids than that of the DInonproducing clone, probably causing both production of the DI genomes and their formation of a stem-loop structure, which serves as an ideal ligand for RIG-I. These results suggested that the integrity of mononegaviral nucleocapsids might be a critical factor in avoiding the undesirable recognition of infection by host cells.

    DOI: 10.1128/JVI.02094-17

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  • Influence of Endogenous Viral Sequences on Gene Expression. Reviewed

    Sofuku K, Honda T

    Gene Expression and Regulation in Mammalian Cells   67 - 80   2018

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  • Importance of Promyelocytic Leukema Protein (PML) for Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication. Reviewed International journal

    Md Golzar Hossain, Eriko Ohsaki, Tomoyuki Honda, Keiji Ueda

    Frontiers in microbiology   9   2324 - 2324   2018

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    Many DNA virus replication-related proteins are associated with promyelocytic leukemia protein (PML), a component of nuclear domain 10 (ND10), which has been investigated for its potential involvement in viral replication. In the case of Kaposi's sarcoma-associated herpesvirus (KSHV) lytic gene products, K8 (K-bZIP), ORF59, and ORF75 have been shown to colocalize with PML, but its importance in KSHV lytic replication is still unclear. In this study, we analyzed the functional influence of PML on KSHV latency and lytic replication in KSHV-infected primary effusion lymphoma (PEL) cell lines. Stable PML-knockout (BC3-PMLKO) and PML-overexpressing BC3 cells (BC3PML) were successfully generated and the latency and reactivation status were analyzed. The results demonstrated that neither KSHV latency nor the episome copy number was affected in BC3-PMLKO cells. In the reactivation phase, the expression dynamics of KSHV immediate-early or early lytic proteins such as RTA, K9 (vIRF1), K5, K3, ORF59, and K8 (K-bZIP) were comparable between wild-type, control BC3, and BC3-PMLKO cells. Interestingly, KSHV lytic replication, virion production, and expression of late genes were downregulated in BC3-PMLKO cells and upregulated in BC3PML cells, compared to those in control or wild-type BC3 cells. Moreover, exogenous PML increased the size of the PML dots and recruited additional K8 (K-bZIP) to PML-NBs as dots. Therefore, PML would function as a positive regulator for KSHV lytic DNA replication by recruiting KSHV replication factors such as 8 (K-bZIP) or ORF59 to the PML-NBs.

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  • Potential Links between Hepadnavirus and Bornavirus Sequences in the Host Genome and Cancer Reviewed

    Tomoyuki Honda

    FRONTIERS IN MICROBIOLOGY   8   2537   2017.12

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    Various viruses leave their sequences in the host genomes during infection. Such events occur mainly in retrovirus infection but also sometimes in DNA and non-retroviral RNA virus infections. If viral sequences are integrated into the genomes of germ line cells, the sequences can become inherited as endogenous viral elements (EVEs). The integration events of viral sequences may have oncogenic potential. Because proviral integrations of some retroviruses and/or reactivation of endogenous retroviruses are closely linked to cancers, viral insertions related to non-retroviral viruses also possibly contribute to cancer development. This article focuses on genomic viral sequences derived from two non-retroviral viruses, whose endogenization is already reported, and discusses their possible contributions to cancer. Viral insertions of hepatitis B virus play roles in the development of hepatocellular carcinoma. Endogenous bornavirus-like elements, the only non-retroviral RNA virus-related EVEs found in the human genome, may also be involved in cancer formation. In addition, the possible contribution of the interactions between viruses and retrotransposons, which seem to be a major driving force for generating EVEs related to non-retroviral RNA viruses, to cancers will be discussed. Future studies regarding the possible links described here may open a new avenue for the development of novel therapeutics for tumor virus-related cancers and/or provide novel insights into EVE functions.

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  • Linkage between the leader sequence and leader RNA production in Borna disease virus-infected cells Reviewed

    Tomoyuki Honda, Kozue Sofuku, Shohei Kojima, Yusuke Yamamoto, Naohiro Ohtaki, Keizo Tomonaga

    VIROLOGY   510   104 - 110   2017.10

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    The 3'-untranslated region (UTR) of the non-segmented, negative-strand (NNS) RNA viral genome is called the leader sequence, and functions as the promoter for viral replication and transcription. NNS RNA viruses also use the sequence as a template to synthesize leader RNAs (leRNAs) with unknown functions. Borna disease virus (BDV) is unique because it establishes a persistent infection and replicates in the nucleus. No report has yet demonstrated the presence of leRNAs during BDV infection. Here, we report that BDV synthesizes leRNAs from the 3'-UTR of the genome. They started at position 5 in the 3'-UTR and ended by the transcription start signal of the nucleoprotein gene. The level of leRNA production is not correlated with the levels of viral replication and transcription. On the other hand, mutation of the 3'-UTR affects leRNA production. Our findings add a novel viral transcript to the BDV life cycle and shed light on BDV replication and/or transcription.

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  • Detection of Antibodies against Borna Disease Virus Proteins in an Autistic Child and Her Mother (vol 70, pg 225, 2017) Reviewed

    Tomoyuki Honda, Kozue Sofuku, Hidenori Matsunaga, Masaya Tachibana, Ikuko Mohri, Masako Taniike, Keizo Tomonaga

    JAPANESE JOURNAL OF INFECTIOUS DISEASES   70 ( 5 )   599 - 599   2017.9

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  • Generation of a non-transmissive Borna disease virus vector lacking both matrix and glycoprotein genes Reviewed

    Kan Fujino, Yusuke Yamamoto, Takuji Daito, Akiko Makino, Tomoyuki Honda, Keizo Tomonaga

    MICROBIOLOGY AND IMMUNOLOGY   61 ( 9 )   380 - 386   2017.9

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    Borna disease virus (BoDV), a prototype of mammalian bornavirus, is a non-segmented, negative strand RNA virus that often causes severe neurological disorders in infected animals, including horses and sheep. Unique among animal RNA viruses, BoDV transcribes and replicates non-cytopathically in the cell nucleus, leading to establishment of long-lasting persistent infection. This striking feature of BoDV indicates its potential as an RNA virus vector system. It has previously been demonstrated by our team that recombinant BoDV (rBoDV) lacking an envelope glycoprotein (G) gene develops persistent infections in transduced cells without loss of the viral genome. In this study, a novel non-transmissive rBoDV, rBoDV MG, which lacks both matrix (M) and G genes in the genome, is reported. rBoDV-MG expressing green fluorescence protein (GFP), rBoDV MG-GFP, was efficiently generated in Vero/MG cells stably expressing both BoDV M and G proteins. Infection with rBoDV MG-GFP was persistently maintained in the parent Vero cells without propagation within cell culture. The optimal ratio of M and G for efficient viral particle production by transient transfection of M and G expression plasmids into cells persistently infected with rBoDV MG-GFP was also demonstrated. These findings indicate that the rBoDV MG-based BoDV vector may provide an extremely safe virus vector system and could be a novel strategy for investigating the function of M and G proteins and the host range of bornaviruses.

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  • Antiviral activity of favipiravir (T-705) against mammalian and avian bornaviruses Reviewed

    Tomoya Tokunaga, Yusuke Yamamoto, Madoka Sakai, Keizo Tomonaga, Tomoyuki Honda

    ANTIVIRAL RESEARCH   143   237 - 245   2017.7

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    Bornaviruses, non-segmented, negative-strand RNA viruses, are emerging agents with the potential for causing various types of neurological symptoms. Previous studies have shown that ribavirin, a nucleic acid analog with broad-spectrum antiviral activity, has a potent antiviral effect on infections with a mammalian bornavirus, Borna disease virus (BoDV-1), as well as avian bornaviruses. However, ribavirin based treatment does not eliminate bornaviruses from persistently infected cells and viral replication resumes after treatment cessation. Therefore, the development of a novel effective anti-bornavirus treatment is needed. To identify such agents, we screened nucleoside/nucleotide mimetics for agents with anti-bornavirus activity. We used Vero cells infected with recombinant BoDV-1 carrying Gaussia luciferase to monitor BoDV-1 replication and found that favipiravir (T-705) is a potent inhibitor of BoDV1 replication. T-705 suppressed BoDV-1 replication in a dose-and time-dependent manner during the observation period of 4 weeks. Notably, no increase in luciferase activity or in the number of BoDV-1positive cells was detected in the at least 4 weeks following T-705 removal. Finally, we demonstrated that T-705 effectively suppressed viral replication of both BoDV-1 and an avian bornavirus, suggesting that T-705 may have a strong antiviral activity against a broad range of bornaviruses. Our findings provide a novel and effective option for treating persistent bornavirus infection. (C) 2017 Elsevier B.V. All rights reserved.

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  • The P gene of rodent brain-adapted measles virus plays a critical role in neurovirulence Reviewed

    Tetsuro Arai, Yuri Terao-Muto, Shotaro Uchida, Che Lin, Tomoyuki Honda, Akiko Takenaka, Fusako Ikeda, Hiroki Sato, Misako Yoneda, Chieko Kai

    JOURNAL OF GENERAL VIROLOGY   98 ( 7 )   1620 - 1629   2017.7

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    In rare cases, measles virus (MV) in children leads to fatal neurological complications such as primary measles encephalitis, post-acute measles encephalitis, subacute sclerosing panencephalitis and measles inclusion-body encephalitis. To investigate the pathogenesis of MV-induced encephalitis, rodent brain-adapted MV strains CAM/RB and CAMR40 were generated. These strains acquired mutations to adapt to the rodent brain during 40 passages in rat brain. However, it is still unknown which genes confer the neurovirulence of MV. We previously established a rescue system for recombinant MVs possessing the backbone of wild-type strain HL, an avirulent strain in mice. In the present study, to identify the genes in CAMR40 that elicit neurovirulence, we generated chimeric recombinant MVs based on strain HL. As a result, recombinant wild-type MV in which the haemagglutinin (H) gene was substituted with that of CAMR40 caused a non-lethal mild disease in mice, while additional substitution of the HL phosphoprotein (P) gene with that of strain CAMR40 caused lethal severe neurological signs comparable to those of CAMR40. These results clearly indicated that, in addition to the H gene, the P gene is required for the neurovirulence of MV CAMR40.

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  • 突然の健忘で発症し精神症状等を合併した抗ボルナウイルス抗体陽性の2症例 Reviewed

    松永 秀典, 陸 馨仙, 福本 素由己, 金井 講治, 近江 翼, 大村 夕美, 本田 知之, 朝長 啓造

    精神神経学雑誌   ( 2017特別号 )   S504 - S504   2017.6

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  • Detection of Antibodies against Borna Disease Virus Proteins in an Autistic Child and Her Mother Reviewed

    Tomoyuki Honda, Kozue Sofuku, Hidenori Matsunaga, Masaya Tachibana, Ikuko Mohri, Masako Taniike, Keizo Tomonaga

    JAPANESE JOURNAL OF INFECTIOUS DISEASES   70 ( 2 )   225 - 227   2017.3

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  • Borna Disease Virus Assembles Porous Cage-like Viral Factories in the Nucleus Reviewed

    Yuya Hirai, Yasuhiro Hirano, Atsushi Matsuda, Yasushi Hiraoka, Tomoyuki Honda, Keizo Tomonaga

    JOURNAL OF BIOLOGICAL CHEMISTRY   291 ( 50 )   25789 - 25798   2016.12

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    Animal-derived RNA viruses frequently generate viral factories in infected cells. However, the details of how RNA viruses build such intracellular structures are poorly understood. In this study, we examined the structure and formation of the viral factories, called viral speckle of transcripts (vSPOTs), that are produced in the nuclei of host cells by Borna disease virus (BDV). Super-resolution microscopic analysis showed that BDV assembled vSPOTs as intranuclear cage-like structures with 59-180-nm pores. The viral nucleoprotein formed the exoskeletons of vSPOTs, whereas the other viral proteins appeared to be mainly localized within these structures. In addition, stochastic optical reconstruction microscopy revealed that filamentous structures resembling viral ribonucleoprotein complexes (RNPs) appeared to protrude from the outer surfaces of the vSPOTs. We also found that vSPOTs disintegrated into RNPs concurrently with the breakdown of the nuclear envelope during mitosis. These observations demonstrated that BDV generates viral replication factories whose shape and formation are regulated, suggesting the mechanism of the integrity of RNA virus persistent infection in the nucleus.

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  • Measles virus induces persistent infection by autoregulation of viral replication Reviewed

    Tomomitsu Doi, Hyun-Jeong Kwon, Tomoyuki Honda, Hiroki Sato, Misako Yoneda, Chieko Kai

    SCIENTIFIC REPORTS   6   37163   2016.11

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    Natural infection with measles virus (MV) establishes lifelong immunity. Persistent infection with MV is likely involved in this phenomenon, as non-replicating protein antigens never induce such long-term immunity. Although MV establishes stable persistent infection in vitro and possibly in vivo, the mechanism by which this occurs is largely unknown. Here, we demonstrate that MV changes the infection mode from lytic to non-lytic and evades the innate immune response to establish persistent infection without viral genome mutation. We found that, in the persistent phase, the viral RNA level declined with the termination of interferon production and cell death. Our analysis of viral protein dynamics shows that during the establishment of persistent infection, the nucleoprotein level was sustained while the phosphoprotein and large protein levels declined. The ectopic expression of nucleoprotein suppressed viral replication, indicating that viral replication is self-regulated by nucleoprotein accumulation during persistent infection. The persistently infected cells were able to produce interferon in response to poly I:C stimulation, suggesting that MV does not interfere with host interferon responses in persistent infection. Our results may provide mechanistic insight into the persistent infection of this cytopathic RNA virus that induces lifelong immunity.

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  • ドイツで死亡した3人の脳炎患者から発見されたカワリリスボルナウイルス(VSBV-1)に対する抗体測定の試み

    松永 秀典, 本田 知之, 近江 翼, 陸 馨仙, 福本 素由己, 金井 講治, 大村 夕美, 朝長 啓造

    NEUROINFECTION   21 ( 2 )   207 - 207   2016.9

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  • Sequence determination of a new parrot bornavirus-5 strain in Japan: implications of clade-specific sequence diversity in the regions interacting with host factors Reviewed

    Ryo Komorizono, Akiko Makino, Masayuki Horie, Tomoyuki Honda, Keizo Tomonaga

    MICROBIOLOGY AND IMMUNOLOGY   60 ( 6 )   437 - 441   2016.6

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    In this study, the genome sequence of a new parrot bornavirus-5 (PaBV-5) detected in Eclectus roratus was determined. Phylogenetic analysis showed that the genus Bornavirus is divided into three major clades and that PaBV-5 belongs to clade 2, which contains avian viruses that exhibit infectivity to mammalian cells. Sequence comparisons of the regions known to interact with host factors indicated that the clade 2 avian viruses possess sequences intermediate between the clade 1 mammalian viruses and the clade 3 avian viruses, suggesting that the identified regions might contribute to the differences in virological properties between the three clades.

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  • An RNA-dependent RNA polymerase gene in bat genomes derived from an ancient negative-strand RNA virus Reviewed

    Masayuki Horie, Yuki Kobayashi, Tomoyuki Honda, Kan Fujino, Takumi Akasaka, Claudia Kohl, Gudrun Wibbelt, Kristin Muehldorfer, Andreas Kurth, Marcel A. Mueller, Victor M. Corman, Nadine Gillich, Yoshiyuki Suzuki, Martin Schwemmle, Keizo Tomonaga

    SCIENTIFIC REPORTS   6   25873   2016.5

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    Endogenous bornavirus-like L (EBLL) elements are inheritable sequences derived from ancient bornavirus L genes that encode a viral RNA-dependent RNA polymerase (RdRp) in many eukaryotic genomes. Here, we demonstrate that bats of the genus Eptesicus have preserved for more than 11.8 million years an EBLL element named eEBLL-1, which has an intact open reading frame of 1,718 codons. The eEBLL-1 coding sequence revealed that functional motifs essential for mononegaviral RdRp activity are well conserved in the EBLL-1 genes. Genetic analyses showed that natural selection operated on eEBLL-1 during the evolution of Eptesicus. Notably, we detected efficient transcription of eEBLL-1 in tissues from Eptesicus bats. To the best of our knowledge, this study is the first report showing that the eukaryotic genome has gained a riboviral polymerase gene from an ancient virus that has the potential to encode a functional RdRp.

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  • Links between Human LINE-1 Retrotransposons and Hepatitis Virus-Related Hepatocellular Carcinoma Reviewed

    Tomoyuki Honda

    FRONTIERS IN CHEMISTRY   4   21   2016.5

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    Hepatocellular carcinoma (HCC) accounts for approximately 80% of liver cancers, the third most frequent cause of cancer mortality. The most prevalent risk factors for HCC are infections by hepatitis B or hepatitis C virus. Findings suggest that hepatitis virus-related HCC might be a cancer in which LINE-1 retrotransposon, often termed L1, activity plays a potential role. Firstly, hepatitis viruses can suppress host defense factors that also control L1 mobilization. Secondly, many recent studies also have indicated that hypomethylation of L1 affects the prognosis of HCC patients. Thirdly, endogenous L1 retrotransposition was demonstrated to activate oncogenic pathways in HCC. Fourthly, several L1 chimeric transcripts with host or viral genes are found in hepatitis virus-related HCC. Such lines of evidence suggest a linkage between L1 retrotransposons and hepatitis virus-related HCC. Here, I briefly summarize current understandings of the association between hepatitis virus-related HCC and L1. Then, I discuss potential mechanisms of how hepatitis viruses drive the development of HCC via L1 retrotransposons. An increased understanding of the contribution of L1 to hepatitis virus-related HCC may provide unique insights related to the development of novel therapeutics for this disease.

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  • Long-term expression of miRNA for RNA interference using a novel vector system based on a negative-strand RNA virus Reviewed

    Tomoyuki Honda, Yusuke Yamamoto, Takuji Daito, Yusuke Matsumoto, Akiko Makino, Keizo Tomonaga

    SCIENTIFIC REPORTS   6   26154   2016.5

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    RNA interference (RNAi) has emerged as a promising technique for gene therapy. However, the safe and long-term expression of small RNA molecules is a major concern for the application of RNAi therapies in vivo. Borna disease virus (BDV), a non-segmented, negative-strand RNA virus, establishes a persistent infection without obvious cytopathic effects. Unique among animal non-retroviral RNA viruses, BDV persistently establishes a long-lasting persistent infection in the nucleus. These features make BDV ideal for RNA virus vector persistently expressing small RNAs. Here, we demonstrated that the recombinant BDV (rBDV) containing the miR-155 precursor, rBDV-miR-155, persistently expressed miR-155 and efficiently silenced its target gene. The stem region of the miR-155 precursor in rBDV-miR-155 was replaceable by any miRNA sequences of interest and that such rBDVs efficiently silence the expression of target genes. Collectively, BDV vector would be a novel RNA virus vector enabling the long-term expression of miRNAs for RNAi therapies.

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  • Influenza A Virus-Induced Expression of a GalNAc Transferase, GALNT3, via MicroRNAs Is Required for Enhanced Viral Replication Reviewed

    Shoko Nakamura, Masayuki Horie, Tomo Daidoji, Tomoyuki Honda, Mayo Yasugi, Atsushi Kuno, Toshihisa Komori, Daisuke Okuzaki, Hisashi Narimatsu, Takaaki Nakaya, Keizo Tomonaga

    JOURNAL OF VIROLOGY   90 ( 4 )   1788 - 1801   2016.2

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    Influenza A virus (IAV) affects the upper and lower respiratory tracts and rapidly induces the expression of mucins, which are common O-glycosylated proteins, on the epithelial surfaces of the respiratory tract. Although mucin production is associated with the inhibition of virus transmission as well as characteristic clinical symptoms, little is known regarding how mucins are produced on the surfaces of respiratory epithelial cells and how they affect IAV replication. In this study, we found that two microRNAs (miRNAs), miR-17-3p and miR-221, which target GalNAc transferase 3 (GALNT3) mRNA, are rapidly downregulated in human alveolar basal epithelial cells during the early stage of IAV infection. We demonstrated that the expression of GALNT3 mRNA is upregulated in an IAV replication-dependent fashion and leads to mucin production in bronchial epithelial cells. A lectin microarray analysis revealed that the stable expression of GALNT3 by human alveolar basal epithelial cells induces mucin-type O-glycosylation modifications similar to those present in IAV-infected cells, suggesting that GALNT3 promotes mucin-type O-linked glycosylation in IAV-infected cells. Notably, analyses using short interfering RNAs and miRNA mimics showed that GALNT3 knockdown significantly reduces IAV replication. Furthermore, IAV replication was markedly decreased in embryonic fibroblast cells obtained from galnt3-knockout mice. Interestingly, IAV-infected galnt3-knockout mice exhibited high mortality and severe pathological alterations in the lungs compared to those of wild-type mice. Our results demonstrate not only the molecular mechanism underlying rapid mucin production during IAV infection but also the contribution of O-linked glycosylation to the replication and propagation of IAV in lung cells.

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  • Endogenous non-retroviral RNA virus elements evidence a novel type of antiviral immunity Reviewed

    Tomoyuki Honda, Keizo Tomonaga

    Mobile Genetic Elements   6 ( 3 )   e1165785   2016

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    Vertebrate genomes contain many virus-related sequences derived from both retroviruses and nonretroviral RNA and DNA viruses. Such non-retroviral RNA sequences are possibly produced by reverse-transcription and integration of viral mRNAs of ancient RNA viruses using retrotransposon machineries. We refer to this process as transcript reversion. During an ancient bornavirus infection, transcript reversion may have left bornavirus-related sequences, known as endogenous bornaviruslike nucleoproteins (EBLNs), in the genome. We have recently demonstrated that all Homo sapiens EBLNs are expressed in at least one tissue. Because species with EBLNs appear relatively protected against infection by a current bornavirus, Borna disease virus, it is speculated that EBLNs play some roles in antiviral immunity, as seen with some endogenous retroviruses. EBLNs can function as dominant negative forms of viral proteins, small RNAs targeting viral sequences, or DNA or RNA elements modulating the gene expression. Growing evidence reveals that various RNA viruses are reverse-transcribed and integrated into the genome of infected cells, suggesting transcript reversion generally occurs during ongoing infection. Considering this, transcript reversion-mediated interference with related viruses may be a novel type of antiviral immunity in vertebrates. Understanding the biological significance of transcript reversion will provide novel insights into host defenses against viral infections.

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  • Possible roles of endogenous RNA virus elements in RNA virus infection. Reviewed

    Honda T, Tomonaga K

    Uirusu   66 ( 1 )   39 - 46   2016

  • 内在性RNAウイルスエレメントによるウイルスRNA制御仮説

    本田 知之, 朝長 啓造

    ウイルス   66 ( 1 )   39 - 46   2016

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  • X-linked RNA-binding motif protein (RBMX) is required for the maintenance of Borna disease virus nuclear viral factories Reviewed

    Yuya Hirai, Tomoyuki Honda, Akiko Makino, Yuzo Watanabe, Keizo Tomonaga

    JOURNAL OF GENERAL VIROLOGY   96 ( 11 )   3198 - 3203   2015.10

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    Borna disease virus (BDV) is a non-segmented, negative-strand RNA virus that establishes persistent infection in the nucleus. Although BDV forms viral inclusion bodies, termed viral speckles of transcripts (vSPOTs), which are associated with chromatin in the nucleus, the host factors involved in the maintenance of vSPOTs remain largely unknown. In this study, we identified X-linked RNA-binding motif protein (RBMX) as a nuclear factor interacting with BDV nucleoprotein. Interestingly, knockdown of RBMX led to disruption of the formation of vSPOTs and reduced both transcription and replication of BDV. Our results indicate that RBMX is involved in the maintenance of the structure of the virus factory in the nucleus.

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  • piRNAs derived from ancient viral processed pseudogenes as transgenerational sequence-specific immune memory in mammals Reviewed

    Nicholas F. Parrish, Kan Fujino, Yusuke Shiromoto, Yuka W. Iwasaki, Hongseok Ha, Jinchuan Xing, Akiko Makino, Satomi Kuramochi-Miyagawa, Toru Nakano, Haruhiko Siomi, Tomoyuki Honda, Keizo Tomonaga

    RNA   21 ( 10 )   1691 - 1703   2015.10

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    Endogenous bornavirus-like nucleoprotein elements (EBLNs) are sequences within vertebrate genomes derived from reverse transcription and integration of ancient bornaviral nucleoprotein mRNA via the host retrotransposon machinery. While species with EBLNs appear relatively resistant to bornaviral disease, the nature of this association is unclear. We hypothesized that EBLNs could give rise to antiviral interfering RNA in the form of PIWI-interacting RNAs (piRNAs), a class of small RNA known to silence transposons but not exogenous viruses. We found that in both rodents and primates, which acquired their EBLNs independently some 25-40 million years ago, EBLNs are present within piRNA-generating regions of the genome far more often than expected by chance alone (P = 8 x 10(-3) -6 x 10(-8)). Three of the seven human EBLNs fall within annotated piRNA clusters and two marmoset EBLNs give rise to bona fide piRNAs. In both rats and mice, at least two of the five EBLNs give rise to abundant piRNAs in the male gonad. While no EBLNs are syntenic between rodent and primate, some of the piRNA clusters containing EBLNs are; thus we deduce that EBLNs were integrated into existing piRNA clusters. All true piRNAs derived from EBLNs are antisense relative to the proposed ancient bornaviral nucleoprotein mRNA. These observations are consistent with a role for EBLN-derived piRNA-like RNAs in interfering with ancient bornaviral infection. They raise the hypothesis that retrotransposon-dependent virus-to-host gene flow could engender RNA-mediated, sequence-specific antiviral immune memory in metazoans analogous to the CRISPR/Cas system in prokaryotes.

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  • Transcription Profiling Demonstrates Epigenetic Control of Non-retroviral RNA Virus-Derived Elements in the Human Genome Reviewed

    Kozue Sofuku, Nicholas F. Parrish, Tomoyuki Honda, Keizo Tomonaga

    CELL REPORTS   12 ( 10 )   1548 - 1554   2015.9

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    Endogenous bornavirus-like nucleoprotein elements (EBLNs) are DNA sequences in vertebrate genomes formed by the retrotransposon-mediated integration of ancient bornavirus sequence. Thus, EBLNs evidence a mechanism of retrotransposon-mediated RNA-to-DNA information flow from environment to animals. Although EBLNs are non-transposable, they share some features with retrotransposons. Here, to test whether hosts control the expression of EBLNs similarly to retrotransposons, we profiled the transcription of all Homo sapiens EBLNs (hsEBLN-1 to hsEBLN-7). We could detect transcription of all hsEBLNs in at least one tissue. Among them, hsEBLN-1 is transcribed almost exclusively in the testis. In most tissues, expression from the hsEBLN-1 locus is silenced epigenetically. Finally, we showed the possibility that hsEBLN-1 integration at this locus affects the expression of a neighboring gene. Our results suggest that hosts regulate the expression of endogenous non-retroviral virus elements similarly to how they regulate the expression of retrotransposons, possibly contributing to new transcripts and regulatory complexity to the human genome.

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  • IFN-beta-inducing, unusual viral RNA species produced by paramyxovirus infection accumulated into distinct cytoplasmic structures in an RNA-type-dependent manner Reviewed

    Asuka Yoshida, Ryoko Kawabata, Tomoyuki Honda, Keizo Tomonaga, Takemasa Sakaguchi, Takashi Irie

    FRONTIERS IN MICROBIOLOGY   6   804   2015.8

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    The interferon (IFN) system is one of the most important defensive responses of mammals against viruses, and is rapidly evoked when the pathogen-associated molecular patterns (PAMPs) of viruses are sensed. Non-self, virus-derived RNA species have been identified as the PAMPs of RNA viruses. In the present study, we compared different types of IFN-beta-inducing and -non-inducing viruses in the context of Sendai virus infection. We found that some types of unusual viral RNA species were produced by infections with IFN-beta-inducing viruses and accumulated into distinct cytoplasmic structures in an RNA-type-dependent manner. One of these structures was similar to the so-called antiviral stress granules (avSGs) formed by an infection with IFN-inducing viruses whose C proteins were knocked-out or mutated. Non-encapsidated, unusual viral RNA harboring the 5'-terminal region of the viral genome as well as RIG-I and typical SG markers accumulated in these granules. Another was a non-SG-like inclusion formed by an infection with the Cantell strain; a copyback-type DI genome, but not an authentic viral genome, specifically accumulated in the inclusion, whereas RIG-I and SG markers did not. The induction of IFN-beta was closely associated with the production of these unusual RNAs as well as the formation of the cytoplasmic structures.

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  • Borna disease virus possesses an NF-kappa B inhibitory sequence in the nucleoprotein gene Reviewed

    Akiko Makino, Kan Fujino, Nicholas F. Parrish, Tomoyuki Honda, Keizo Tomonaga

    SCIENTIFIC REPORTS   5   8696   2015.3

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    Borna disease virus (BDV) has a non-segmented, negative-stranded RNA genome and causes persistent infection in many animal species. Previous study has shown that the activation of the I kappa B kinase (IKK)/NF-kappa B pathway is reduced by BDV infection even in cells expressing constitutively active mutant IKK. This result suggests that BDV directly interferes with the IKK/NF-kappa B pathway. To elucidate the mechanism for the inhibition of NF-kappa B activation by BDV infection, we evaluated the cross-talk between BDV infection and the NF-kappa B pathway. Using Multiple EM for Motif Elicitation analysis, we found that the nucleoproteins of BDV (BDV-N) and NF-kappa B1 share a common ankyrin-like motif. When THP1-CD14 cells were pre-treated with the identified peptide, NF-kappa B activation by Toll-like receptor ligands was suppressed. The 20S proteasome assay showed that BDV-N and BDV-N-derived peptide inhibited the processing of NF-kappa B1 p105 into p50. Furthermore, immunoprecipitation assays showed that BDV-N interacted with NF-kappa B1 but not with NF-kappa B2, which shares no common motif with BDV-N. These results suggest BDV-N inhibits NF-kappa B1 processing by the 20S proteasome through its ankyrin-like peptide sequence, resulting in the suppression of IKK/NF-kappa B pathway activation. This inhibitory effect of BDV on the induction of the host innate immunity might provide benefits against persistent BDV infection.

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  • Neuropathogenesis of persistent infection with Borna disease virus. Reviewed

    Honda T

    Uirusu   65 ( 1 )   145 - 154   2015

  • ボルナ病ウイルスの神経病原性に関する研究

    本田 知之

    ウイルス   65 ( 1 )   145 - 154   2015

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  • ボルナ病ウイルス感染症の病態研究

    本田 知之, 朝長 啓造

    化学療法の領域   31 ( 4 )   640 - 647   2015

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  • Heat stress is a potent stimulus for enhancing rescue efficiency of recombinant Borna disease virus Reviewed

    Shohei Kojima, Tomoyuki Honda, Yusuke Matsumoto, Keizo Tomonaga

    MICROBIOLOGY AND IMMUNOLOGY   58 ( 11 )   636 - 642   2014.11

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    Recently developed vector systems based on Borna disease virus (BDV) hold promise as platforms for efficient and stable gene delivery to the central nervous system (CNS). However, because it currently takes several weeks to rescue recombinant BDV (rBDV), an improved rescue procedure would enhance the utility of this system. Heat stress reportedly enhances the rescue efficiency of other recombinant viruses. Here, heat stress was demonstrated to increase the amount of BDV genome in persistently BDV-infected cells without obvious cytotoxicity. Further analyses suggested that the effect of heat stress on BDV infection is not caused by an increase in the activity of BDV polymerase. More cells in which BDV replication occurs were obtained in the initial phase of rBDV rescue by using heat stress than when it was not used. Thus, heat stress is a useful improvement on the published rescue procedure for rBDV. The present findings may accelerate the practical use of BDV vector systems in basic science and the clinic and thus enable broader adoption of this viral vector, which is uniquely suited for gene delivery to the CNS.

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  • Inhibition of Borna disease virus replication by an endogenous bornavirus-like element in the ground squirrel genome Reviewed

    Kan Fujino, Masayuki Horie, Tomoyuki Honda, Dana K. Merriman, Keizo Tomonaga

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   111 ( 36 )   13175 - 13180   2014.9

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    Animal genomes contain endogenous viral sequences, such as endogenous retroviruses and retrotransposons. Recently, we and others discovered that nonretroviral viruses also have been endogenized in many vertebrate genomes. Bornaviruses belong to the Mononegavirales and have left endogenous fragments, called "endogenous bornavirus-like elements" (EBLs), in the genomes of many mammals. The striking features of EBLs are that they contain relatively long ORFs which have high sequence homology to the extant bornavirus proteins. Furthermore, some EBLs derived from bornavirus nucleoprotein (EBLNs) have been shown to be transcribed as mRNA and probably are translated into proteins. These features lead us to speculate that EBLs may function as cellular coopted genes. An EBLN element in the genome of the thirteen-lined ground squirrel (Ictidomys tridecemlineatus), itEBLN, encodes an ORF with 77% amino acid sequence identity to the current bornavirus nucleoprotein. In this study, we cloned itEBLN from the ground squirrel genome and investigated its involvement in Borna disease virus (BDV) replication. Interestingly, itEBLN, but not a human EBLN, colocalized with the viral factory in the nucleus and appeared to affect BDV polymerase activity by being incorporated into the viral ribonucleoprotein. Our data show that, as do certain endogenous retroviruses, itEBLN potentially may inhibit infection by related exogenous viruses in vivo.

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  • ボルナウイルス

    本田 知之

    別冊日本臨床 新領域別症候群シリーズ「神経症候群Ⅰ」   26   637 - 640   2013.12

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  • Nucleocytoplasmic Shuttling of Viral Proteins in Borna Disease Virus Infection Reviewed

    Tomoyuki Honda, Keizo Tomonaga

    VIRUSES-BASEL   5 ( 8 )   1978 - 1990   2013.8

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    Nuclear import and export of viral RNA and proteins are critical to the replication cycle of viruses that replicate in the nucleus. Borna disease virus (BDV) is a nonsegmented, negative-strand RNA virus that belongs to the order Mononegavirales. BDV has several distinguishing features, one of the most striking being the site of its replication. BDV RNA is transcribed and replicated in the nucleus, while most other negative-strand RNA viruses replicate in the cytoplasm. Therefore, the nucleocytoplasmic trafficking of BDV macromolecules plays a key role in virus replication. Growing evidence indicates that several BDV proteins, including the nucleoprotein, phosphoprotein, protein X and large protein, contribute to the nucleocytoplasmic trafficking of BDV ribonucleoprotein (RNP). The directional control of BDV RNP trafficking is likely determined by the ratios of and interactions between the nuclear localization signals and nuclear export signals in the RNP. In this review, we present a comprehensive view of several unique mechanisms that BDV has developed to control its RNP trafficking and discuss the significance of BDV RNP trafficking in the replication cycle of BDV.

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  • Pathogenesis of Encephalitis Caused by Persistent Measles Virus Infection. Reviewed

    Honda T, Yoneda M, Sato H, Kai C

    Encephalitis   251 - 262   2013

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  • Host Molecular Chaperones: Cell Surface Receptors for Viruses. Reviewed

    Honda T, Tomonaga K

    Heat Shock Proteins   7   293 - 307   2013

  • Evolutionarily Conserved Interaction between the Phosphoproteins and X Proteins of Bornaviruses from Different Vertebrate Species Reviewed

    Kan Fujino, Masayuki Horie, Tomoyuki Honda, Shoko Nakamura, Yusuke Matsumoto, Ivo M. B. Francischetti, Keizo Tomonaga

    PLOS ONE   7 ( 12 )   e51161   2012.12

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    Bornavirus, a non-segmented, negative-strand RNA viruses, is currently classified into several genetically distinct genotypes, such as Borna disease virus (BDV) and avian bornaviruses (ABVs). Recent studies revealed that bornavirus genotypes show unique sequence variability in the putative 5' untranslated region (5' UTR) of X/P mRNA, a bicistronic mRNA for the X protein and phosphoprotein (P). In this study, to understand the evolutionary relationship among the bornavirus genotypes, we investigated the functional interaction between the X and P proteins of four bornavirus genotypes, BDV, ABV genotype 4 and 5 and reptile bornavirus (RBV), the putative 5' UTRs of which exhibit variation in the length. Immunofluorescence and immunoprecipitation analyses using mammalian and avian cell lines revealed that the X proteins of bornaviruses conserve the ability to facilitate the export of P from the nucleus to the cytoplasm via interaction with P. Furthermore, we showed that inter-genotypic interactions may occur between X and P among the genotypes, except for X of RBV. In addition, a BDV minireplicon assay demonstrated that the X and P proteins of ABVs, but not RBV, can affect the polymerase activity of BDV. This study demonstrates that bornaviruses may have conserved the fundamental function of a regulatory protein during their evolution, whereas RBV has evolved distinctly from the other bornavirus genotypes.

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  • Generation of Human Bronchial Epithelial Cell Lines Expressing Inactive Mutants of GALNT3 Reviewed

    Shoko Nakamura, Masayuki Horie, Kan Fujino, Yusuke Matsumoto, Tomoyuki Honda, Keizo Tomonaga

    JOURNAL OF VETERINARY MEDICAL SCIENCE   74 ( 11 )   1493 - 1496   2012.11

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    As a tool to understand the role of mucins in the infection of respiratory viruses, we established cell lines stably expressing inactive mutants of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), which initiates O-glycosylation of mucins. We introduced single amino acid mutation into the regions essential for the enzyme activity of GALNT3 using the expression plasmid of human GALNT3 and transfected the mutant constructs into a human bronchial epithelial cell line, BEAS-2B. We showed that although the mutants of GALNT3 exhibit an authentic localization at the Golgi apparatus, the glycosylation pattern of the expressing cell lines appeared to be different from that of the cells expressing wild-type GALNT3. These results suggested that the established cell lines express inactive forms of GALNT3 and might be useful in investigation of the significance of O-glycosylation of mucins in respiratory virus infections.

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  • Bornavirus Closely Associates and Segregates with Host Chromosomes to Ensure Persistent Intranuclear Infection Reviewed

    Yusuke Matsumoto, Yohei Hayashi, Hiroko Omori, Tomoyuki Honda, Takuji Daito, Masayuki Horie, Kazuyoshi Ikuta, Kan Fujino, Shoko Nakamura, Urs Schneider, Geoffrey Chase, Tamotsu Yoshimori, Martin Schwemmle, Keizo Tomonaga

    CELL HOST & MICROBE   11 ( 5 )   492 - 503   2012.5

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    Bornaviruses are nonsegmented negative-strand RNA viruses that establish a persistent infection in the nucleus and occasionally integrate a DNA genome copy into the host chromosomal DNA. However, how these viruses achieve intranuclear infection remains unclear. We show that Borna disease virus (BDV), a mammalian bornavirus, closely associates with the cellular chromosome to ensure intranuclear infection. BDV generates viral factories within the nucleus using host chromatin as a scaffold. In addition, the viral ribonucleoprotein (RNP) interacts directly with the host chromosome throughout the cell cycle, using core histones as a docking platform. HMGB1, a host chromatin-remodeling DNA architectural protein, is required to stabilize RNP on chromosomes and for efficient BDV RNA transcription in the nucleus. During metaphase, the association of RNP with mitotic chromosomes allows the viral RNA to segregate into daughter cells and ensure persistent infection. Thus, bornaviruses likely evolved a chromosome-dependent life cycle to achieve stable intranuclear infection.

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  • Detection of Avian bornavirus 5 RNA in Eclectus roratus with feather picking disorder Reviewed

    Masayuki Horie, Kengo Ueda, Akiko Ueda, Tomoyuki Honda, Keizo Tomonaga

    MICROBIOLOGY AND IMMUNOLOGY   56 ( 5 )   346 - 349   2012.5

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    Avian bornavirus (ABV) was discovered recently in parrots with proventricular dilatation disease (PDD), a fatal neurological disease. Although ABV has been shown to be a causative agent of PDD, its virological characteristics are largely unknown. Here we report the detection of ABV genotype 5 RNA in an Eclectus roratus with feather picking disorder (FPD). Interestingly, although the bird was persistently infected with ABV5 for at least 8 months, it had no clinical signs of PDD. Although it remains unclear whether ABV5 is associated with FPD, these findings raise the importance of epidemiological studies of birds with diseases other than PDD.

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  • Morbillivirus receptors and tropism: multiple pathways for infection Reviewed

    Hiroki Sato, Misako Yoneda, Tomoyuki Honda, Chieko Kai

    FRONTIERS IN MICROBIOLOGY   3   75   2012

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    Morbilliviruses, which include measles virus (MeV), canine distemper virus, and rinderpest virus, are among the most important pathogens in their respective hosts and cause severe syndromes. Morbilliviruses are enveloped viruses with two envelope proteins, one of which is hemagglutinin (H) protein, which plays a role in binding to cellular receptors. During morbillivirus infection, the virus initially targets lymphoid cells and replicates efficiently in the lymph nodes. The principal cellular receptor for morbillivirus is signaling lymphocyte activation molecule (SLAM, also called CD150), which is exclusively expressed on immune cells. This feature reflects the strong lymphoid cell tropism and viral spread in the infected body. Morbillivirus infection, however, affects various tissues in the body, including the lung, kidney, gastrointestinal tract, vascular endothelium, and brain. Thus, other receptors for morbilliviruses in addition to SLAM might exist. Recently, nectin-4 has been identified as a novel epithelial cell receptor for MeV. The expression of nectin-4 is localized to polarized epithelial cells, and this localization supports the notion of cell tropism since MeV also grows well in the epithelial cells of the respiratory tract. Although two major receptors for lymphoid and epithelial cells in natural infection have been identified, morbillivirus can still infect many other types of cells with low infectivity, suggesting the existence of inefficient but ubiquitously expressed receptors. We have identified other molecules that are implicated in morbillivirus infection of SLAM-negative cells by alternative mechanisms. These findings indicate that morbillivirus utilizes multiple pathways for establishment of infection. These studies will advance our understanding of morbillivirus tropism and pathogenesis.

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  • A Novel Borna Disease Virus Vector System That Stably Expresses Foreign Proteins from an Intercistronic Noncoding Region Reviewed

    Takuji Daito, Kan Fujino, Tomoyuki Honda, Yusuke Matsumoto, Yohei Watanabe, Keizo Tomonaga

    JOURNAL OF VIROLOGY   85 ( 23 )   12170 - 12178   2011.12

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    Borna disease virus (BDV), a nonsegmented, negative- strand RNA virus, infects a wide variety of mammalian species and readily establishes a long- lasting, persistent infection in brain cells. Therefore, this virus could be a promising candidate as a novel RNA virus vector enabling stable gene expression in the central nervous system (CNS). Previous studies demonstrated that the 5&apos; untranslated region of the genome is the only site for insertion and expression of a foreign gene. In this study, we established a novel BDV vector in which an additional transcription cassette has been inserted into an intercistronic noncoding region between the viral phosphoprotein (P) and matrix (M) genes. The recombinant BDV (rBDV) carrying green fluorescent protein (GFP) between the P and M genes, rBDV P/ M- GFP, expressed GFP efficiently in cultured cells and rodent brains for a long period of time without attenuation. Furthermore, we generated a nonpropagating rBDV, Delta GLLP/M, which lacks the envelope glycoprotein (G) and a splicing intron within the polymerase gene (L), by the transcomplementation system with either transient or stable expression of the G gene. Interestingly, rBDV Delta GLLP/M established a persistent infection in cultured cells with stable expression of GFP in the absence of the expression of G. Using persistently infected rBDV Delta GLLP/M-infected cells, we determined the amino acid region in the cytoplasmic tail (CT) of BDV G important for the release of infectious rBDV particles and also demonstrated that the CT region may be critical for the generation of pseudotyped rBDV having vesicular stomatitis virus G protein. Our results revealed that the newly established BDV vector constitutes an alternative tool not only for stable expression of foreign genes in the CNS but also for understanding the mechanism of the release of enveloped virions.

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  • Recombinant vaccines against the mononegaviruses-What we have learned from animal disease controls Reviewed

    Hiroki Sato, Misako Yoneda, Tomoyuki Honda, Chieko Kai

    VIRUS RESEARCH   162 ( 1-2 )   63 - 71   2011.12

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    The mononegaviruses include a number of highly contagious and severe disease-causing viruses of both animals and humans. For the control of these viral diseases, development of vaccines, either with classical methods or with recombinant DNA virus vectors, has been attempted over the years. Recently reverse genetics of mononegaviruses has been developed and used to generate infectious viruses possessing genomes derived from cloned cDNA in order to study the consequent effects of viral gene manipulations on phenotype. This technology allows us to develop novel candidate vaccines. In particular, a variety of different attenuation strategies to produce a range of attenuated mononegavirus vaccines have been studied. In addition, because of their ideal nature as live vaccines, recombinant mononegaviruses expressing foreign proteins have also been produced with the aim of developing multivalent vaccines against more than one pathogen. These recombinant mononegaviruses are currently under evaluation as new viral vectors for vaccination. Reverse genetics could have great potential for the preparation of vaccines against many mononegaviruses. (C) 2011 Elsevier B.V. All rights reserved.

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  • Upregulation of Insulin-Like Growth Factor Binding Protein 3 in Astrocytes of Transgenic Mice That Express Borna Disease Virus Phosphoprotein Reviewed

    Tomoyuki Honda, Kan Fujino, Daisuke Okuzaki, Naohiro Ohtaki, Yusuke Matsumoto, Masayuki Horie, Takuji Daito, Masayuki Itoh, Keizo Tomonaga

    JOURNAL OF VIROLOGY   85 ( 9 )   4567 - 4571   2011.5

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    In a previous study, we demonstrated that transgenic mice that express Borna disease virus (BDV) phosphoprotein (P) in astrocytes show striking neurobehavioral abnormalities resembling those in BDV-infected animals. To understand the molecular disturbances induced by the expression of P in astrocytes, we performed microarray analysis with cultured astroglial cells transiently expressing P. We showed that expression of insulin-like growth factor binding protein 3 mRNA increases not only in P-expressing cultured cells but also in astrocytes from the cerebella of P transgenic mice (P-Tg). Furthermore, we demonstrated that insulin-like growth factor signaling is disturbed in the P-Tg cerebellum, a factor that might be involved in the increased vulnerability of Purkinje cell neurons in the brain.

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  • Endogenous non-retroviral RNA virus elements in mammalian genomes Reviewed

    Masayuki Horie, Tomoyuki Honda, Yoshiyuki Suzuki, Yuki Kobayashi, Takuji Daito, Tatsuo Oshida, Kazuyoshi Ikuta, Patric Jern, Takashi Gojobori, John M. Coffin, Keizo Tomonaga

    NATURE   463 ( 7277 )   84 - U90   2010.1

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    Retroviruses are the only group of viruses known to have left a fossil record, in the form of endogenous proviruses, and approximately 8% of the human genome is made up of these elements(1,2). Although many other viruses, including non-retroviral RNA viruses, are known to generate DNA forms of their own genomes during replication(3-5), none has been found as DNA in the germline of animals. Bornaviruses, a genus of non-segmented, negative-sense RNA virus, are unique among RNA viruses in that they establish persistent infection in the cell nucleus(6-8). Here we show that elements homologous to the nucleoprotein (N) gene of bornavirus exist in the genomes of several mammalian species, including humans, non-human primates, rodents and elephants. These sequences have been designated endogenous Borna-like N (EBLN) elements. Some of the primate EBLNs contain an intact open reading frame (ORF) and are expressed as mRNA. Phylogenetic analyses showed that EBLNs seem to have been generated by different insertional events in each specific animal family. Furthermore, the EBLN of a ground squirrel was formed by a recent integration event, whereas those in primates must have been formed more than 40 million years ago. We also show that the N mRNA of a current mammalian bornavirus, Borna disease virus (BDV), can form EBLN-like elements in the genomes of persistently infected cultured cells. Our results provide the first evidence for endogenization of non-retroviral virus-derived elements in mammalian genomes and give novel insights not only into generation of endogenous elements, but also into a role of bornavirus as a source of genetic novelty in its host.

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  • Molecular Chaperone BiP Interacts with Borna Disease Virus Glycoprotein at the Cell Surface Reviewed

    Tomoyuki Honda, Masayuki Horie, Takuji Daito, Kazuyoshi Ikuta, Keizo Tomonaga

    JOURNAL OF VIROLOGY   83 ( 23 )   12622 - 12625   2009.12

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    Borna disease virus (BDV) is characterized by highly neurotropic infection. BDV enters its target cells using virus surface glycoprotein (G), but the cellular molecules mediating this process remain to be elucidated. We demonstrate here that the N-terminal product of G, GP1, interacts with the 78-kDa chaperone protein BiP. BiP was found at the surface of BDV-permissive cells, and anti-BiP antibody reduced BDV infection as well as GP1 binding to the cell surface. We also reveal that BiP localizes at the synapse of neurons. These results indicate that BiP may participate in the cell surface association of BDV.

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  • Heat shock cognate protein 70 controls Borna disease virus replication via interaction with the viral non-structural protein X Reviewed

    Yohei Hayashi, Masayuki Horie, Takuji Daito, Tomoyuki Honda, Kazuyoshi Ikuta, Keizo Tomonaga

    MICROBES AND INFECTION   11 ( 3 )   394 - 402   2009.3

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    Borna disease virus (BDV) is a non-segmented, negative-sense RNA virus and has the property of persistently infecting the cell nucleus. BDV encodes a 10-kDa non-structural protein, X, which is a negative regulator of viral polymerase activity but is essential for virus propagation. Recently, we have demonstrated that interaction of X with the viral polymerase cofactor, phosphoprotein (P), facilitates translocation of P from the nucleus to the cytoplasm. However, the mechanism by which the intracellular localization of X is controlled remains unclear. In this report, we demonstrate that BDV X interacts with the 71 kDa molecular chaperon protein, Hsc70. Immunoprecipitation assays revealed that Hsc70 associates with the same region of X as P and, interestingly, that expression of P interferes competitively with the interaction between X and Hsc70. A heat shock experiment revealed that BDV X translocates into the nucleus, dependent upon the nuclear accumulation of Hsc70. Furthermore, we show that knockdown of Hsc70 by short interfering RNA decreases the nuclear localization of both X and P and markedly reduces the expression of viral genomic RNA in persistently infected cells. These data indicate that Hsc70 may be involved in viral replication by regulating the intracellular distribution of X. (C) 2009 Elsevier Masson SAS. All rights reserved.

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  • PASK (proline-alanine-rich Ste20-related kinase) binds to tubulin and microtubules and is involved in microtubule stabilization Reviewed

    Tomonari Tsutsumi, Takamitsu Kosaka, Hiroshi Ushiro, Kazushi Kimura, Tomoyuki Honda, Tetsuro Kayahara, Akira Mizoguchi

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   477 ( 2 )   267 - 278   2008.9

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    Proline-alanine-rich Ste20-related kinase (PASK, also referred to as SPAK) has been linked to ion transport regulation. Here, we report two novel activities of PASK: binding to tubulin and microtubules and the promotion of microtubule assembly. Tubulin binding assay showed that full-length PASK and its kinase domain bound to purified tubulin whereas the N-terminal or C-terminal non-catalytic domains of PASK did not. The full-length PASK and its kinase domain were sedimented with paclitaxel-stabilized microtubules by ultracentrifugation. These results indicate that the kinase domain of PASK can interact directly with both microtubules and soluble tubulin in vitro. Truncated PASK lacking the N-terminal non-catalytic domain promoted microtubule assembly at a subcritical concentration of purified tubulin. FLAG-PASK expressed in COS-7 cells translocated to the cytoskeleton when the cells were stimulated with hypertonic sodium chloride, and stabilized microtubules against depolymerization by nocodazole. Our findings suggest that PASK may regulate the cytoskeleton by modulating microtubule stability. (C) 2008 Elsevier Inc. All rights reserved.

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  • Dipole source analysis of temporal slow waves in the elderly Reviewed

    Eishi Motomura, Koji Inui, Hiroyuki Ogawa, Shinji Nakase, Kenji Hamanaka, Tomoyuki Honda, Takashi Shiroyama, Takuya Matsumoto, Teruhisa Komori, Motohiro Okada, Ryusuke Kakigi

    NEUROPSYCHOBIOLOGY   57 ( 1-2 )   9 - 13   2008

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    Background: Temporal low-voltage irregular delta-waves (TLID) are often found in elderly subjects. The physiological significance of TLID has not been clarified; however, our previous studies suggest that TLID are associated with mild cerebrovascular dysfunction. Objective: The present study aimed to reveal the origin of TLID and their neural mechanisms by dipole source modeling. Methods: From electroencephalography records taken from 21 scalp electrodes, clear and typical TLID of 6 elderly subjects ( mean age, 69 8 6.2 years) were selected. Among these, we selected and averaged 7-12 clear TLID on the left side in each subject, and estimated a single equivalent current dipole for the averaged TLID. Results: The best equivalent current dipoles were estimated to be located in the medial part of the temporal lobe in or near the parahippocampal gyrus in the hemisphere ipsilateral to the TLID, with a high reliability in all subjects. Conclusions: Considering the source localization of TLID, TLID seem to indicate certain dysfunctions of the hippocampus 7or adjacent regions. This is the first study to report the cerebral origin of TLID and suggest its physiological Copyright (c) 2008 S. Karger AG, Basel.

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  • Interneurite affinity is regulated by heterophilic nectin interactions in concert with the cadherin machinery Reviewed

    Hideru Togashi, Jun Miyoshi, Tomoyuki Honda, Toshiaki Sakisaka, Yoshimi Takai, Masatoshi Takeichi

    JOURNAL OF CELL BIOLOGY   174 ( 1 )   141 - 151   2006.7

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    Neurites recognize their specific partners during the formation of interneuronal connections. In hippocampal pyramidal neurons, axons attach to dendrites for their synaptogenesis, but the dendrites do not form stable contacts with each other, suggesting the presence of a mechanism to allow their selective associations. Nectin-1 (N1), an immunoglobulin domain adhesive protein, is preferentially localized in axons, and its heterophilic partner, N3, is present in both axons and dendrites; we tested their potential roles in interneurite recognition. The overexpression of N1, causing its mislocalization to dendrites, induced atypical dendrodendritic as well as excessive axodendritic associations. On the contrary, the genetic deletion of N1 loosened the contacts between axons and dendritic spines. Those actions of nectins required cadherin-catenin activities, but the overexpression of cadherin itself could not accelerate neurite attachment. These results suggest that the axon-biased localization of N1 and its transinteraction with N3 in cooperation with the cadherin machinery is critical for the ordered association of axons and dendrites.

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  • Involvement of nectins in the formation of puncta adherentia junctions and the mossy fiber trajectory in the mouse hippocampus Reviewed

    T Honda, T Sakisaka, T Yamada, N Kumazawa, T Hoshino, M Kajita, T Kayahara, H Ishizaki, M Tanaka-Okamoto, A Mizoguchi, T Manabe, J Miyoshi, Y Takai

    MOLECULAR AND CELLULAR NEUROSCIENCE   31 ( 2 )   315 - 325   2006.2

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    Synapses are specialized intercellular junctions whose specificity and plasticity are mediated by synaptic cell adhesion molecules. In hippocampus, the mossy fibers form synapses on the apical dendrites of the CA3 pyramidal cells where synaptic and puncta adherentia junctions (PAJs) are highly developed. Synaptic junctions are the sites of neurotransmission, while PAJs are regarded as mechanical adhesion sites. Cell-cell adhesion molecules nectin-1 and nectin-3 asymmetrically localize at the pre- and post-synaptic sides of PAJs, respectively. TO reveal the definitive role of nectins, we analyzed nectin-1(-/-) and nectin-3(-/-) mice. In both the mutant mice, the number of PAJs at the synapses between the mossy fiber terminals and the dendrites of the CA3 pyramidal cells was reduced. In addition, the abnormal mossy fiber trajectory was observed. These results indicate that nectins are involved in the formation of PAJs, which maintain the proper mossy fiber trajectory. (c) 2005 Elsevier Inc. All rights reserved.

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  • 神経シナプス形成におけるネクチンの役割

    溝口 明, 木村 一志, 本田 知之, 高井 義美

    Molecular Medicine   42 ( 12 )   1330 - 1336   2006

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  • 復職デイケアの可能性

    伊藤 雅之, 本田 知之, 森 豊和, 杉本 淳子, 河津 雄一郎, 岡崎 裕士

    臨床精神医学   35 ( 8 )   1079 - 1083   2006

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  • Activation of Cdc42 by trans interactions of the cell adhesion molecules nectins through c-Src and Cdc42-GEF FRG Reviewed

    T Fukuhara, K Shimizu, T Kawakatsu, T Fukuyama, Y Minami, T Honda, T Hoshino, T Yamada, H Ogita, M Okada, Y Takai

    JOURNAL OF CELL BIOLOGY   166 ( 3 )   393 - 405   2004.8

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    Nectins, Ca2+-independent immunoglobulin-like cell-cell adhesion molecules, initiate cell-cell adhesion by their trans interactions and recruit cadherins to cooperatively form adherens junctions (AJs). In addition, the trans interactions of nectins induce the activation of Cdc42 and Rac small G proteins, which increases the velocity of the formation of AJs. We examined here how nectins induce the activation of Cdc42 in MDCK epithelial cells and L fibroblasts. Nectins recruited and activated c-Src at the nectin-based cell-cell adhesion sites. FRG, a GDP/GTP exchange factor specific for Cdc42, was then recruited there, tyrosine phosphorylated by c-Src, and activated, causing an increase in the GTP-bound active form of Cdc42. Inhibition of the nectin-induced activation of c-Src suppressed the nectin-induced activation of FRG and Cdc42. Inhibition of the nectin-induced activation of FRG or depletion of FRG by RNA interference suppressed the nectin-induced activation of Cdc42. These results indicate that nectins induce the activation of Cdc42 through c-Src and FRG locally at the nectin-based cell-cell adhesion sites.

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  • A novel role of nectins in inhibition of the e-cadherin-induced activation of Rac and formation of cell-cell adherens junctions Reviewed

    T Hoshino, K Shimizu, T Honda, T Kawakatsu, T Fukuyama, T Nakamura, M Matsuda, Y Takai

    MOLECULAR BIOLOGY OF THE CELL   15 ( 3 )   1077 - 1088   2004.3

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    Nectins are Ca2+-independent immunoglobulin (Ig)-like cell-cell adhesion molecules. The trans-interactions of nectins recruit cadherins to the nectin-based cell-cell adhesion, resulting in formation of cell-cell adherens junctions (AJs) in epithelial cells and fibroblasts. The trans-interaction of E-cadherin induces activation of Rac small G protein, whereas the trans-interactions of nectins induce activation of not only Rac but also Cdc42 small G protein. We showed by the fluorescent resonance energy transfer (FRET) imaging that the trans-interaction of E-cadherin induced dynamic activation and inactivation of Rac, which led to dynamic formation and retraction of lamellipodia. Moreover, we found here that the nectins, which did not trans-interact with other nectins (non-trans-interacting nectins), inhibited the E-cadherin-induced activation of Rac and reduced the velocity of the formation of the E-cadherin-based cell-cell AJs. The inhibitory effect of non-trans-interacting nectins was suppressed by the activation of Cdc42 induced by the trans-interactions of nectins. These results indicate a novel role of nectins in regulation of the E-cadherin-induced activation of Rac and formation of cell-cell AJs.

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  • Regulation by nectin of the velocity of the formation of adherens junctions,and tight junctions Reviewed

    T Honda, K Shimizu, A Fukuhara, K Irie, Y Takai

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   306 ( 1 )   104 - 109   2003.6

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    Cadherins are key Ca2+-dependent cell-cell adhesion molecules at adherens junctions (AJs) in fibroblasts and epithelial cells, whereas claudins are key Ca2+-independent cell-cell adhesion molecules at tight junctions (TJs) in epithelial cells. The formation and maintenance of TJs are dependent on the formation and maintenance of AJs. Nectins are Ca2+-independent immunoglobulin-like cell-cell adhesion molecules which comprise a family of four members, nectin-1, -2, -3, and -4, and are involved in the formation of AJs in cooperation with cadherins, and the subsequent formation of TJs. We show here that the velocity of the formation of the E-cadherin-based AJs is increased by overexpression of nectin-1 and is reduced by addition of the nectin-1 inhibitors to the medium in L cells stably expressing E-cadherin and Madin-Darby canine kidney cells. Moreover, the velocity of the formation of the claudin-based TJs is increased by overexpression of nectin-1 and is reduced by addition of the nectin-1 inhibitors to the medium in Madin-Darby canine kidney cells. These results indicate that nectins regulate the velocity of the formation of the E-cadherin-based AJs and the subsequent formation of the claudin-based TJs. (C) 2003 Elsevier Science (USA). All rights reserved.

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  • Cdc42 and Rac small G proteins activated by trans- interactions of nectins are involved in activation of c-Jun N-terminal kinase, but not in association of nectins and cadherin to form adherens junctions, in fibroblasts Reviewed

    T Honda, K Shimizu, T Kawakatsu, A Fukuhara, K Irie, T Nakamura, M Matsuda, Y Takai

    GENES TO CELLS   8 ( 5 )   481 - 491   2003.5

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    Background: Nectins are Ca2+-independent immunoglobulin-like cell-cell adhesion molecules which associate with cadherins to form adherens junctions (AJs) in epithelial cells and fibroblasts. Nectin-1 and -3 are members of the nectin family which most strongly trans -interact, causing cell-cell adhesion. The trans -interaction between nectin-1 and -3 induces the activation of both Cdc42 and Rac small G proteins in epithelial cells. We studied the roles of Cdc42 and Rac activated in this way in L fibroblasts stably expressing both nectin-1 and E-cadherin (nectin-1-EL cells).
    Results: The trans-interaction between nectin-1 and -3 induced the activation of Cdc42 and Rac in nectin-1-EL cells. Cdc42, and presumably Rac, activated in this way, induced the activation of c-Jun N-terminal kinase (JNK), but not p38 mitogen-activated protein (MAP) kinase or extracellular signal-regulated kinase (ERK). Cdc42 or Rac was not essential for the association of nectin-1 and E-cadherin to form AJs. Reorganization of the actin cytoskeleton was not required for the association of nectin-1 and E-cadherin.
    Conclusion: These results indicate that Cdc42 and Rac activated by the trans -interaction of nectins selectively induce the activation of JNK, but are not essential for the association of nectins and cadherin to form AJs in fibroblasts.

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  • Role of each immunoglobulin-like loop of nectin for its cell-cell adhesion activity Reviewed

    M Yasumi, K Shimizu, T Honda, M Takeuchi, Y Takai

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   302 ( 1 )   61 - 66   2003.2

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    Nectins are Ca2+-independent immunoglobulin (Ig)-like cell-cell adhesion molecules that form cell-cell junctions, cooperatively with or independently of cadherins, in a variety of cells. Nectins comprise a family of four members, nectin-1, -2, -3, and -4. All nectins have one extracellular region with three Ig-like loops, one transmembrane segment, and one cytoplasmic tail. It has been shown mainly by use of cadherin-deficient L fibroblasts stably expressing each nectin that nectins first form homo-cis-dimers and then homoor hetero-trans-dimers, causing cell-cell adhesion, and that the formation of the cis-dimers is necessary for the formation of the transdimers. However, kinetics of the formation of these dimers have not been examined biochemically by use of pure nectin proteins. We prepared here pure recombinant proteins of extracellular fragments of nectin-3 containing various combinations of Ig-like loops, all of which were fused to the Fc portion of IgG and formed homo-cis-dimers through the Fc portion, and of an extracellular fragment of nectin-1 containing three Ig-like loops which was fused to secreted alkaline phosphatase and formed homo-cis-dimers. We showed here by use of these proteins that the first Ig-like loop of nectin-3 was essential and sufficient for the formation of trans-dimers with nectin-1, but that the second Ig-like loop of nectin-3 was furthermore necessary for its cell-cell adhesion activity. (C) 2003 Elsevier Science (USA). All rights reserved.

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  • Antagonistic and agonistic effects of an extracellular fragment of nectin on formation of E-cadherin-based cell-cell adhesion Reviewed

    T Honda, K Shimizu, T Kawakatsu, M Yasumi, T Shingai, A Fukuhara, K Ozaki-Kuroda, K Irie, H Nakanishi, Y Takai

    GENES TO CELLS   8 ( 1 )   51 - 63   2003.1

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    Background: Nectin is a Ca2+ -independent immunoglobulin-like cell-cell adhesion molecule at the E-cadherin-based cell-cell adherens junctions (AJs), and comprises a family consisting of four members, nectin-1, -2, -3, and -4. Nectin and E-cadherin are associated with afadin and alpha-catenin, actin filament (F-actin)-binding proteins connecting respective adhesion molecules to the actin cytoskeleton, but the role of nectin in the formation of the E-cadherin-based cell-cell AJs has not yet been fully understood. To obtain evidence for this role of nectin, we attempted to develop an antagonist and/or agonist of nectin.
    Results: We made a recombinant extracellular fragment of nectin-3 (Nef-3). Nef-3 trans -interacted with cellular nectin-1 and thereby diminished the formation of the nectin-1-based cell-cell adhesion. This resulted in a reduction of the formation of the E-cadherin-based cell-cell adhesion in L fibroblasts stably expressing both exogenous nectin-1alpha and E-cadherin (nectin-1-EL cells) and MDCK cells stably expressing exogenous nectin-1alpha (nectin-1-MDCK cells). This antagonistic effect of Nef-3 was also observed in L cells stably expressing exogenous E-cadherin alone (EL cells) and wild-type MDCK cells. Conversely, Nef-3 coated on microbeads first recruited the nectin-afadin complex and then the E-cadherin-catenin complex to the bead-cell contact sites in nectin-1-EL and nectin-1-MDCK cells.
    Conclusion: These results suggest that nectin is necessary and sufficient for the recruitment of E-cadherin to the nectin-based cell-cell adhesion sites and involved in the formation of E-cadherin-based cell-cell AJs.

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  • trans-interactions of nectins induce formation of filopodia and lamellipodia through the respective activation of Cdc42 and Rac small G proteins Reviewed

    T Kawakatsu, K Shimizu, T Honda, T Fukuhara, T Hoshino, Y Takai

    JOURNAL OF BIOLOGICAL CHEMISTRY   277 ( 52 )   50749 - 50755   2002.12

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    Nectins and afadin constitute a novel cell-cell adhesion system that plays a cooperative role with cadherins in the organization of adherens junctions (AJs). Nectins are Ca2+-independent immunoglobulin-like cell-cell adhesion molecules, and afadin is a nectin- and actin filament-binding protein that connects nectins to the actin cytoskeleton. Rac and Cdc42 small G proteins have been implicated in the organization of AJs, but their modes of action remain unknown. The trans-interaction of E-cadherin has recently been shown to induce the activation of Rac, but not that of Cdc42. We show here that the trans-interactions of nectins induce the formation of filopodia and lamellipodia through the respective activation of Cdc42 and Rac. The Cdc42 activation is necessary, but not sufficient, for the Rac-induced formation of lamellipodia, whereas the Rac activation is not necessary for the Cdc42-induced formation of filopodia. These effects of nectins require their cytoplasmic tail but not their association with afadin. We propose here the functional relationship between nectins and the small G proteins in the organization of AJs.

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  • Role of nectin in organization of tight junctions in epithelial cells Reviewed

    A Fukuhara, K Irie, A Yamada, T Katata, T Honda, K Shimizu, H Nakanishi, Y Takai

    GENES TO CELLS   7 ( 10 )   1059 - 1072   2002.10

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    Background: In polarized epithelial cells, cell-cell adhesion forms specialized membrane structures comprised of claudin-based tight junctions (TJs) and of E-cadherin-based adherens junctions (AJs). These structures are aligned from the apical to the basal side of the lateral membrane, but the mechanism of this organization remains unknown. Nectin is a Ca2+ independent immunoglobulin-like cell-cell adhesion molecule which localizes at AJs. Nectin is associated with E-cadherin through their respective cytoplasmic tail-binding proteins, afadin and catenins, and involved in the formation of AJs in cooperation with E-cadherin. We show here that nectin is also involved in the formation of TJs.
    Results: During the formation of the junctional complex consisting of AJs and TJs in Madin-Darby canine kidney (MDCK) cells, claudin and occludin accumulated at the apical sites of the nectin-based cell-cell adhesion sites. This accumulation of claudin and occludin was inhibited by inhibitors acting on the trans interaction of nectin. The barrier function of TJs was also impaired by the nectin inhibitors. It has been shown that a phorbol ester promotes the formation of a TJ-like structure in an E-cadherin-independent manner. This phorbol ester-induced formation of the TJ-like structure was also inhibited by the nectin inhibitors.
    Conclusions: These results suggest a role of the nectin-afadin system in the organization of TJs as well as AJs in epithelial cells.

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  • Involvement of nectin in the localization of junctional adhesion molecule at tight junctions Reviewed

    A Fukuhara, K Irie, H Nakanishi, K Takekuni, T Kawakatsu, W Ikeda, A Yamada, T Katata, T Honda, T Sato, K Shimizu, H Ozaki, H Horiuchi, T Kita, Y Takai

    ONCOGENE   21 ( 50 )   7642 - 7655   2002.10

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    Junctional adhesion molecule (JAM) is a Ca2+-independent immunoglobulin-like cell-cell adhesion molecule which localizes at tight junctions (TJs). Claudin is a key cell-cell adhesion molecule that forms TJ strands at TJs. JAM is associated with claudin through their cytoplasmic tail-binding protein, ZO-1. JAM is furthermore associated with Par-3, a cell polarity protein which forms a ternary complex with Par-6 and atypical protein kinase C. Nectin is another Ca2+-independent immunoglobulin-like cell-cell adhesion molecule which localizes at adherens junctions (AJs). Nectin is associated with E-cadherin through their respective cytoplasmic tail-binding proteins, afadin and catenins, and involved in the formation of AJs cooperatively with E-cadherin. We show here that nectin is furthermore involved in the localization of JAM at TJs. During the formation of the junctional complex consisting of AJs and Us in Madin-Darby canine kidney (MDCK) cells, JAM was recruited to the nectin-based cell-cell adhesion sites. This recruitment of JAM was inhibited by nectin inhibitors, which inhibited the trans-interaction of nectin. Microbeads coated with the extracellular fragment of nectin, that interacted with cellular nectin, also recruited JAM to the bead-MDCK cell contact sites. Furthermore, when cadherin-deficient L fibroblasts stably expressing both exogenous JAM and nectin (nectin-JAM-L cells) were co-cultured with L fibroblasts expressing only nectin (nectin-L cells), JAM was concentrated at the cell-cell adhesion sites between nectin-JAM-L and nectin-L cells without the trans-interaction of JAM. Analyses of the localization and immunoprecipitation of JAM revealed that it was associated with nectin through afadin and ZO-1. These results suggest that nectin has a role in the localization of JAM at Us in the process of the formation of the junctional complex in epithelial cells.

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  • Role of the second immunoglobulin-like loop of nectin in cell-cell adhesion Reviewed

    Y Momose, T Honda, M Inagaki, K Shimizu, K Irie, H Nakanishi, Y Takai

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   293 ( 1 )   45 - 49   2002.4

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    Nectin is a Ca2+-independent immunoglobulin (Ig)-like cell-cell adhesion molecule that forms cell-cell adherens junctions cooperatively with E-cadherin in a variety of cells. Nectin has one transmembrane segment and three Ig-like loops in the extracellular region. The first Ig-like loop is essential for the trans-dimer formation of nectin of two neighboring cells, causing cell-cell adhesion. We show here that the second Ig-like loop is essential for the cis-dimer formation of nectin on the same cell, and that the cis-dimer formation is essential for the trans-dimer formation. (C) 2002 Elsevier Science (USA). All rights reserved.

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  • Nectin: an adhesion molecule involved in formation of synapses Reviewed

    A Mizoguchi, H Nakanishi, K Kimura, K Matsubara, K Ozaki-Kuroda, T Katata, T Honda, Y Kiyohara, K Heo, M Higashi, T Tsutsumi, S Sonoda, C Ide, Y Takai

    JOURNAL OF CELL BIOLOGY   156 ( 3 )   555 - 565   2002.2

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    The nectin-afadin system is a novel cell-cell adhesion system that organizes adherens junctions cooperatively with the cadherin-catenin system in epithelial cells. Nectin is an immunoglobulin-like adhesion molecule, and afadin is an actin filament-binding protein that connects nectin to the actin cytoskeleton. Nectin has four isoforms (-1, -2, -3, and -4). Each nectin forms a homo-cis-dimer followed by formation of a homo-trans-dimer, but nectin-3 furthermore forms a hetero-trans-dimer with nectin-1 or -2, and the formation of each hetero-trans-dimer is stronger than that of each homo-trans-dimer. We show here that at the synapses between the mossy fiber terminals and dendrites of pyramidal cells in the CA3 area of adult mouse hippocampus, the nectin-afadin system colacalizes with the cadherin-catenin system, and nectin-1 and -3 asymmetrically localize at the pre- and postsynaptic sides of puncta adherentia junctions, respectively. During development, nectin-1 and -3 asymmetrically localize not only at puncta adherentia junctions but also at synaptic junctions. Inhibition of the nectin-based adhesion by an inhibitor of nectin-1 in cultured rat hippocampal neurons results in a decrease in synapse size and a concomitant increase in synapse number. These results indicate an important role of the nectin-afadin system in the formation of synapses.

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  • GTP結合タンパク質

    本田 知之, 清水 一也, 中西 宏之, 高井 義美

    実験医学   20 ( 14 )   146 - 152   2002

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  • Complex formation of SMAP/KAP3, a KIF3A/B ATPase motor-associated protein, with a human chromosome-associated polypeptide Reviewed

    K Shimizu, H Shirataki, T Honda, S Minami, Y Takai

    JOURNAL OF BIOLOGICAL CHEMISTRY   273 ( 12 )   6591 - 6594   1998.3

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    We have recently isolated SMAP (Smg GDS-associated protein; Smg GDS: small G protein GDP dissociation stimulator) as a novel Smg GDS-associated protein, which has Armadillo repeats and is phosphorylated by Src tyrosine kinase. SMAP is a human counterpart of mouse KAP3 (kinesin superfamily-associated protein) that is associated with mouse KIF3A/B (a kinesin superfamily protein), which functions as a microtubule-based ATPase motor for organelle transport, We isolated here a SMAP-interacting protein from a human brain cDNA library, identified it to be a human homolog of Xenopus XCAP-E (Xenopus chromosome-associated polypeptide), a subunit of condensins that regulate the assembly and structural maintenance of mitotic chromosomes, and named it HCAP (Human chromosome-associated polypeptide), Tissue and subcellular distribution analyses indicated that HCAP was ubiquitously expressed and highly concentrated in the nuclear fraction, where SMAP and KIF3B were also present, SMAP was extracted as a ternary complex with HCAP and KIF3B from the nuclear fraction in the presence of Mg-ATP. The results suggest that SMAP/KAP3 serves as a linker between HCAP and KIF3A/B in the nucleus, and that SMAP/KAP3 plays a role in the interaction of chromosomes with an ATPase motor protein.

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  • SMAP, an Smg GDS-associating protein having Arm repeats and phosphorylated by Src tyrosine kinase Reviewed

    K Shimizu, H Kawabe, S Minami, T Honda, K Takaishi, H Shirataki, Y Takai

    JOURNAL OF BIOLOGICAL CHEMISTRY   271 ( 43 )   27013 - 27017   1996.10

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    Smg GDS is a regulator having two activities on a group of small G proteins including the Rho and Rap1 family members and Ki-Ras; one is to stimulate their GDP/GTP exchange reactions, and the other is to inhibit their interactions with membranes. Structurally, it has 11 Arm repeats, a protein interaction motif, found in the Drosophila Armadillo protein, a homolog of mammalian beta-catenin. We have isolated here an Smg GDS-interacting protein from a human brain cDNA library by use of the yeast two-hybrid method and named it SMAP (Smg GDS-associated protein). SMAP was a protein with a M(r) of 91,189 and 792 amino acids. SMAP had 9 Arm repeats. Recombinant SMAP interacted with recombinant Smg GDS but did not affect the two activities of Smg GDS on RhoA. SMAP was tyrosine phosphorylated by v-Src, and this phosphorylation reduced the affinity of SMAP for Smg GDS. Tissue and subcellular distribution analyses indicated that SMAP was ubiquitously expressed and highly concentrated at the endoplasmic reticulum area, Searches for sequence homology to SMAP revealed that SMAP was significantly homologous to sea urchin SpKAP115, suggesting that SMAP is a mammalian counterpart of SpKAP115 or its related protein. SpKAP115 is an accessory subunit of sea urchin kinesin II, an ATPase motor that transports vesicles along microtubules. These results suggest that SMAP serves as an adaptor for both Smg GDS and kinesin II or its related protein and links them with both the Smg GDS-regulated small G protein and Src tyrosine kinase signalings.

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  • Development of Borna Disease Virus Vector for Differentiation of Human iPSCs into Skeletal Muscle Cells

    Yumiko Komatsu, Dan Takeuchi, Hidetoshi Sakurai, Yasuhiro Ikeda, Yusuke Yamamoto, Tomoyuki Honda, Akiko Makino, Keizo Tomonaga

    MOLECULAR THERAPY   25 ( 5 )   213 - 213   2017.5

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  • The regulation of Borna disease virus production Reviewed

    Akiko Makino, Tomoyuki Honda, Keizo Tomonaga

    The 14th Awaji International Forum on Infection and Immunity   2015.9

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  • IGF2 is involved in the regulation of Borna disease virus production. Reviewed

    Akiko Makino, Tomoyuki Honda, Keizo Tomonaga

    Negative Strand RNA virus meeting 2015   2015.6

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  • IGF2によるボルナ病ウイルス粒子産生 制御機構の解析 Reviewed

    牧野晶子, 藤野寛, 平井悠哉, 惣福梢, 本田知之, 朝長啓造

    第4回Negative Strand Virus-Japan   2015.1

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  • ボルナ病ウイルス粒子産生に対する宿主因子IGF2の関与 Reviewed

    牧野晶子, 藤野寛, 平井悠哉, 惣福梢, 本田知之, 朝長啓造

    第62回日本ウイルス学会   2014.11

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  • 新規遺伝子トリボルナウイルス(ABV‐BF)の解析

    佐々悠木子, 堀江真行, 鈴木研太, 加藤真樹, 香川紘子, 鈴木和彦, 渋谷淳, CHANATHIP Thammakarn, 竹原一明, 古谷哲也, 本田知之, 朝長啓造, 岡ノ谷一夫, 水谷哲也

    日本獣医学会学術集会講演要旨集   157th   403   2014.8

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  • Expression of IGF2 affects Borna disease virus production in infected cells Reviewed

    Akiko Makino, Kan Fujino, Takuji Daito, Tomoyuki Honda, Keizo Tomonaga

    International Union of Microbiological Societies Congresses   2014.7

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  • ボルナウイルスの粒子産生制御機構の解析 Reviewed

    牧野晶子, 藤野寛, 大東卓史, 本田知之, 朝長啓造

    第3回Negative Strand Virus-Japan   2014.1

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  • ボルナ病ウイルスNタンパク質のアンキリン様配列を介したNF-κ B活性化阻害 Reviewed

    牧野晶子, 藤野寛, 惣福梢, 中村祥子, 本田知之, 朝長啓造

    第61回日本ウイルス学会   2013.11

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  • Inhibition of NF-κB activation by peptide derived from nucleoprotein of Borna disease virus. Reviewed

    Akiko Makino, Kan Fujino, Kozue Sofuku, Shoko Nakamura, Tomoyuki Honda, Keizo Tomonaga

    15th International Negative Strand Virus Meeting   2013.6

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  • ウイルスタンパク質内のTLRシグナル伝達阻害ペプチドの探索と評価 Reviewed

    牧野晶子, 藤野寛, 惣福梢, 中村祥子, 伊藤睦美, 本田知之, 新矢恭子, 河岡義裕, 朝長啓造

    第六回ボルナウイルス研究会   2013.3

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  • 内在性ボルナ病ウイルス様エレメントによるボルナ病ウイルスの新しい制御機構

    本田知之, 小嶋将平, 牧野晶子, 藤野寛, 惣福梢, 朝長啓造

    日本ウイルス学会学術集会プログラム・抄録集   61st   2013

  • ジリスゲノムより復元した内在性ボルナウイルスはボルナ病ウイルスの感染を阻害する

    藤野寛, 堀江真行, 本田知之, 朝長啓造

    日本ウイルス学会学術集会プログラム・抄録集   61st   2013

  • ボルナウイルスの人への感染と病原性の検討:抗ウイルス剤リバビリンによる治療の試み

    松永秀典, 陸馨仙, 柳田誠, 富岡孝仁, 金井講治, 阪上由香子, 高岡謙吉, 高田宏宗, 木村亮, 本田知之, 朝長啓造

    総合病院精神医学   25 ( Supplement )   2013

  • A型インフルエンザウイルス感染におけるムチン型糖転移酵素GALNT3の機能解析

    中村祥子, 堀江真行, 安木真世, 大道寺智, 久野敦, 奥崎大介, 牧野晶子, 本田知之, 成松久, 中屋隆明, 朝長啓造

    日本分子生物学会年会プログラム・要旨集(Web)   36th   2013

  • A型インフルエンザウイルス感染におけるムチン型糖転移酵素GALNT3の機能解析

    中村祥子, 堀江真行, 安木真世, 大道寺智, 久野敦, 奥崎大介, 牧野晶子, 本田知之, 成松久, 中屋隆明, 朝長啓造

    日本ウイルス学会学術集会プログラム・抄録集   61st   2013

  • A型インフルエンザウイルス感染細胞におけるmiRNAを介したGALNT3の発現制御に関する解析 Reviewed

    中村 祥子, 堀江 真行, 安木 真世, 奥崎 大介, 本田 知之, 朝長 啓造

    日本獣医学会学術集会講演要旨集   153回   229 - 229   2012.3

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  • 内在性ボルナウイルス様Nエレメント1の転写制御機構の解明

    惣福梢, 本田知之, 藤野寛, 堀江真行, 朝長啓造

    日本ウイルス学会学術集会プログラム・抄録集   60th   2012

  • Intranuclear persistence of Borna disease virus shows a novel life cycle of RNA virus using host chromosome. Reviewed

    Matsumoto Y, Fujino K, Horie M, Nakamura S, Honda T, Schwemmle M, Tomonaga K

    The 10th International Student Seminar. Kyoto, 5-8 March 2012   2012

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  • A 型インフルエンザウイルス感染によるムチン型糖転移酵素GALNT3 の発現制御機序と意義 Reviewed

    中村祥子, 堀江真行, 安木真世, 岡崎大介, 牧野晶子, 本田知之, 朝長啓造

    第60 回日本ウイルス学会学術集会. 大阪 2012 年11月13-15 日   2012

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  • ボルナウイルス 感染細胞における核内ウイルスRNP の制御機構の解明 Reviewed

    本田知之, 松本祐介, 牧野晶子, 藤野 寛, 惣福 梢, 中村祥子, 朝長啓造

    第35回日本分子生物学会年会. 福岡 2012 年12月11-14日   2012

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  • 内在性ボルナウイルスEBLN の発現によるボルナ病ウイルスの感染阻害 Reviewed

    藤野 寛, 堀江真行, 本田知之, 大東卓史, 松本祐介, 朝長啓造

    第153 回日本獣医学会学術集会. 埼玉2012 年3月27-29日   2012

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  • ボルナ病ウイル ス核内構造物の存在意義の解明 Reviewed

    本田知之, 松本祐介, 牧野晶子, 藤野 寛, 惣福 梢, 中村祥子, 朝長啓造

    第60回日本ウイルス学会学術集会. 大阪 2012 年 11月13-15日   2012

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  • ヒト由来内在性ボルナウイルス様ヌクレオプロテイン‐2の機能解明 Reviewed

    藤野 寛, 堀江真行, 本田知之, 惣福 梢, 朝長啓造

    第60回日本ウイルス学会学術集会. 大阪 2012 年11月13-15日   2012

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  • The discovery of endogenous non-retroviral RNA virus elements and their endogenization process. Reviewed

    Horie M, Kobayashi Y, Honda T, Suzuki Y, Gojobori T, Tomonaga K

    第6回研究所ネットワーク国際シンポジウム. 東京. 2011年6月9日   2011

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  • ボルナウイルスを用いた新規RNAウイルスベクターの開発

    大東卓史, 堀江真行, 藤野寛, 松本祐介, 本田知之, 朝長啓造

    日本RNA学会年会要旨集   12th   2010

  • ボルナ病ウイルスのインテグレーションに関する研究

    堀江真行, 本田知之, 大東卓史, 藤野寛, 松本祐介, 朝長啓造

    日本ウイルス学会学術集会プログラム・抄録集   58th   2010

  • 膜遺伝子欠損型ボルナ病ウイルスベクターの開発

    大東卓史, 松本祐介, 藤野寛, 堀江真行, 本田知之, 朝長啓造

    日本獣医学会学術集会講演要旨集   149th   2010

  • 鳥ボルナウイルスXおよびP遺伝子の相互作用の解析

    藤野寛, 堀江真行, 上田謙吾, 本田知之, 大東卓史, 松本祐介, 朝長啓造

    日本獣医学会学術集会講演要旨集   148th   2009

  • ボルナウイルス属ウイルスのXおよびP蛋白質の相互作用の解析

    藤野寛, 堀江真行, 本田知之, 大東卓史, 松本祐介, 生田和良, 朝長啓造

    日本ウイルス学会学術集会プログラム・抄録集   57th   2009

  • ボルナ病ウイルスのクロマチン結合に関与するウイルス因子の同定

    堀江真行, 松本祐介, 本田知之, 大東卓史, 藤野寛, 生田和良, 朝長啓造

    日本ウイルス学会学術集会プログラム・抄録集   57th   2009

  • Tyrosine phosphorylation controls cortactin binding to two enterohaemorrhagic Escherichia coli effectors: Tir and EspFu/TccP

    Vlademir V. Cantarelli, Toshio Kodama, Niels Nijstad, Said Kamal Abolghait, Shigeyuki Nada, Masato Okada, Tetsuya Iida, Takeshi Honda

    CELLULAR MICROBIOLOGY   9 ( 7 )   1782 - 1795   2007.7

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    Enterohaemorrhagic Escherichia coli (EHEC) is an important food-borne pathogen that, upon infection, causes destruction of the microvilli brush border of intestinal cells. EHEC is able to recruit several host cell proteins and induce actin accumulation beneath its adherence site, forming a pedestal-like structure upon which the bacterium is firmly attached. Injection of bacterial effectors into the host cells is required to trigger the recruitment and activation of proteins, such as cortactin, neural Wiskott-Aldrich syndrome protein (N-WASP) and Arp2/3 complex, directly involved in the actin polymerization process. We found that cortactin, an actin-binding protein, has a pivotal role during pedestal formation by EHEC. Cortactin was found to bind directly to two important virulence factors of EHEC, Tir and EspF(u), which are translocated into the host cells during infection. Binding of cortactin to these effectors is dependent upon tyrosine phosphorylation and a balance between tyrosine phosphorylation and dephosphorylation of cortactin is required to regulate pedestal formation by EHEC.

    DOI: 10.1111/j.1462-5822.2007.00913.x

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  • ネクチン(2):E‐カドヘリン依存性細胞間接着形成の制御機構

    星野崇, 清水一也, 本田知之, 川勝智生, 福山泰平, 中村岳史, 松田道行, 高井義美

    日本癌学会総会記事   62nd   106   2003.8

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  • 探索から機能解析へ向かうプロテオミクス時代のタンパク質研究 第2章 タンパク質の分子機能と生物学的機能 3) 生理活性因子とシグナル伝達因子 3 GTP結合タンパク質

    本田知之, 清水一也, 中西宏之, 高井義美

    実験医学   20 ( 14 )   2110 - 2116   2002.9

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  • ネクチン‐アファディン系依存性細胞間接着形成におけるアクチン細胞骨格の役割

    川勝智生, 清水一也, 本田知之, 福原淳範, 福原達朗, 入江賢児, 高井義美

    日本癌学会総会記事   61st   109   2002.8

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  • SMAP結合蛋白質の同定とその性状解析

    本田知之, 清水一也, 南誠剛, 小林芳人, 白瀧博通, 高井義美

    日本分子生物学会年会プログラム・講演要旨集   20th   202   1997.12

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    J-GLOBAL

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  • SMAP: An Smg GDS-associated protein having arm repeats and phosphorylated by v-src tyrosine kinase.

    K Shimizu, H Kawabe, M Yanagida, S Minami, T Honda, Y Takai

    MOLECULAR BIOLOGY OF THE CELL   7   14 - 14   1996.12

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Presentations

  • ボルナウイルス感染症の歴史と今後の展望 Invited

    本田 知之

    令和3年ともえ会総会  2021.10.10 

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  • ヒトにおけるボルナウイルス感染症の実態とその病態 Invited

    本田 知之

    第25回日本神経感染症学会総会・学術大会  2021.10.1 

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  • がん発生におけるLINE-1の役割 Invited

    本田 知之

    第5回転移因子研究会  2021.8.27 

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  • 発がんにおけるがんウイルスとLINE-1の相互作用 Invited

    本田 知之

    23rd Summer Retrovirus Conference  2021.7.2 

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  • Identification of an intranuclear ERV-containing human transcript induced by vaccination International conference

    HONDA Tomoyuki

    The 18th Awaji International Forum on Infection and Immunity  2019.9.12 

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  • Gamma herpesviruses enhance retrotransposition of long interspersed element-1 Invited International conference

    HONDA Tomoyuki

    The 3rd Korea-Japan International Symposium for Transposable Elements  2019.5.14 

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  • Loading of small RNAs derived from an endogenous bornavirus element on the MIWI protein in GC2 cells International conference

    HONDA Tomoyuki

    The 16th Awaji International Forum on Infection and Immunity  2017.9.8 

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  • L1-mediated gene transfer from viruses to the host confers antiviral immunity Invited International conference

    Tomoyuki Honda, Keizo Tomonaga

    The 2nd Japan-Korea International Symposium for Transposable Elements  2017.6.28 

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  • RNAウイルス持続感染におけるウイルス特異的核内構造体の構造、形成、その生理意義 Invited

    本田 知之, 朝長 啓造

    第39回日本分子生物学会年会  2016.11.30 

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  • Analysis of the possible crosstalk between Borna disease virus and LINE-1 Invited International conference

    Tomoyuki Honda, Keizo Tomonaga

    The 1st Korea-Japan International Symposium for Transposable Elements  2016.6.10 

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  • 低分子RNAによる新しいウイルス防御機構の解明とその制御方法の探索 Invited

    本田 知之

    第6回SENRIの会  2016.1.13 

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  • RNAウイルス配列の内在化により宿主が獲得したウイルス抵抗性の解明 Invited

    本田 知之, 朝長 啓造

    第38回日本分子生物学会年会  2015.12.1 

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  • ボルナ病ウイルスの神経病原性に関する研究 Invited

    本田 知之

    第62回日本ウイルス学会学術集会  2014.11.10 

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  • ボルナ病ウイルスと精神疾患 Invited

    本田 知之

    東京大学 精神科セミナー  2014.10.8 

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  • ボルナ病ウイルスと核内宿主機構 Invited

    本田 知之

    第11回ウイルス学キャンプ in 湯河原  2014.9.17 

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  • 核内におけるウイルスRNA検知機構の解明 Invited

    本田 知之

    第2回感染症国際センターシンポジウム  2014.3.18 

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  • ボルナウイルスと宿主細胞との核内における攻防 Invited

    本田 知之

    京都産業大学 生命科学セミナー  2012.11.28 

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  • 持続感染時のモノネガウイルス病原性発現の分子メカニズム Invited

    本田 知之

    京都大学 ウイルス研究所セミナー  2011.8.22 

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Industrial property rights

Awards

  • Best Poster Award

    2015.7   The 10th International Symposium of the Institute Network  

    本田 知之

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  • 日本ウイルス学会杉浦奨励賞

    2014.10   日本ウイルス学会  

    本田 知之

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  • 山村賞

    1999.3   大阪大学医学部  

    本田 知之

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Research Projects

  • Comprehensive analysis of roles of endogenous virome during virus infection

    Grant number:21H02738  2021.04 - 2024.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    本田 知之

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    Authorship:Principal investigator 

    Grant amount:\17420000 ( Direct expense: \13400000 、 Indirect expense:\4020000 )

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  • セシウムがインフルエンザウイルス・RSウイルス感染に及ぼす影響

    Grant number:20K08180  2020.04 - 2023.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    山下 信子, 小川 寛人, 八代 将登, 難波 ひかる, 本田知之

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    Authorship:Coinvestigator(s) 

    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

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  • DNA損傷修復系による核内ウイルス制御の普遍原理の解明

    2018 - 2021

    基盤研究(B) 

    本田 知之

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    Authorship:Principal investigator  Grant type:Competitive

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  • レトロトランスポゾンを介した新しい宿主-RNAウイルス間相互作用の探索と解析

    2015 - 2018

    基盤研究(C) 

    本田 知之

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    Authorship:Principal investigator  Grant type:Competitive

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  • 核内ウイルスRNAに対する宿主認識・応答機構の解明

    2013 - 2015

    新学術領域研究(研究領域提案型) 

    本田 知之

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    Authorship:Principal investigator  Grant type:Competitive

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  • 核内RNAウイルスと宿主DNA損傷の相互作用解析

    2013 - 2015

    若手研究(B) 

    本田 知之

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    Authorship:Principal investigator  Grant type:Competitive

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  • 動物由来RNAウイルスが制御する非コードRNAマシナリーの探索と解析

    2012 - 2014

    新学術領域研究(研究領域提案型) 

    本田 知之

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  • モービリウイルスー宿主間の新しい相互作用機構の解明

    2011 - 2012

    若手研究(B) 

    本田 知之

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    Authorship:Principal investigator  Grant type:Competitive

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  • ウイルスを用いた自閉症小脳病態の分子メカニズムの解明

    2010 - 2011

    研究活動スタート支援 

    本田 知之

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    Authorship:Principal investigator  Grant type:Competitive

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  • ウイルス感染を用いた脳高次機能の制御機構の解明

    2007 - 2010

    特別研究員奨励費 

    本田 知之

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    Authorship:Principal investigator  Grant type:Competitive

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  • Study on pathogenesis of psychiatric disorders using virus infections

    2007

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    Grant type:Competitive

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  • 神経回路網形成におけるシナプス結合の新しい接着機構の解明

    2001 - 2003

    特別研究員奨励費 

    本田 知之

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    Authorship:Principal investigator  Grant type:Competitive

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  • Study on new adhesion mechanism at synapse

    2000 - 2006

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Class subject in charge

  • Virology (2021academic year) special  - その他

  • Practice in Virology (2021academic year) special  - その他

  • Medical Tutorial (2021academic year) 1st semester  - 火2~3

  • Medical Tutorial (2021academic year) 1st semester  - 火2~3

  • Introduction to Medical and Dental Sciences (2021academic year) Concentration  - その他

  • Research in Medical Sciences I (2021academic year) special  - その他

  • Research in Medical Sciences II (2021academic year) special  - その他

  • Combat against Infectious Diseases (2021academic year) Second semester  - 木1~2

  • Research Presentation in Preventive Medicine (2021academic year) special  - その他

  • Research Projects and Practicals: Virology I (2021academic year) special  - その他

  • Lecture and Research Projects: Virology I (2021academic year) special  - その他

  • Research Projects and Practicals: Virology II (2021academic year) special  - その他

  • Lecture and Research Projects: Virology II (2021academic year) special  - その他

  • Research Projects and Practicals: Virology I (2020academic year) special  - その他

  • Lecture and Research Projects: Virology I (2020academic year) special  - その他

  • Research Projects and Practicals: Virology II (2020academic year) special  - その他

  • Lecture and Research Projects: Virology II (2020academic year) special  - その他

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