論文 - 本田　知之

High-level Elevation of Transgene Expression via the Joint Effect of Trichostatin A and D-glucose in a Malignant Pleural Mesothelioma-derived Cell Line Resistant to Adenovirus Vector-based Transgene Expression. 査読

Mori J, Arao Y, Honda T, Kumon H

Journal of Cancer Science & Therapy   16   627   2024年4月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.37421/1948-5956.2024.16.627

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Suppression of Borna Disease Virus Replication during Its Persistent Infection Using the CRISPR/Cas13b System. 査読 国際誌

Shigenori Sasaki, Hirohito Ogawa, Hirokazu Katoh, Tomoyuki Honda

International journal of molecular sciences   25 ( 6 )   2024年3月

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ijms25063523

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HAND2 suppresses favipiravir efficacy in treatment of Borna disease virus infection 査読

Da Teng, Keiji Ueda, Tomoyuki Honda

Antiviral Research   222   105812 - 105812   2024年2月

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担当区分：最終著者,　責任著者   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.antiviral.2024.105812

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SARS-CoV-2 spike receptor-binding domain is internalized and promotes protein ISGylation in human induced pluripotent stem cell-derived cardiomyocytes 査読

Shota Okuno, Shuichiro Higo, Takumi Kondo, Mikio Shiba, Satoshi Kameda, Hiroyuki Inoue, Tomoka Tabata, Shou Ogawa, Yu Morishita, Congcong Sun, Saki Ishino, Tomoyuki Honda, Shigeru Miyagawa, Yasushi Sakata

Scientific Reports   13 ( 1 )   2023年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-023-48084-7

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その他リンク： https://www.nature.com/articles/s41598-023-48084-7

Roles of Human Endogenous Retroviruses and Endogenous Virus-Like Elements in Cancer Development and Innate Immunity 査読

Hirokazu Katoh, Tomoyuki Honda

Biomolecules   13 ( 12 )   1706 - 1706   2023年11月

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/biom13121706

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Impact of Borna Disease Virus Infection on the Transcriptome of Differentiated Neuronal Cells and Its Modulation by Antiviral Treatment

Da Teng, Keiji Ueda, Tomoyuki Honda

Viruses   15 ( 4 )   942 - 942   2023年4月

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/v15040942

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Need for re-evaluating the risk of coronavirus disease 2019 transmission to neonates. 査読 国際誌

Kazuhiro Uda, Mitsuru Tsuge, Masato Yashiro, Tomoyuki Honda, Hirokazu Tsukahara

Pediatrics international : official journal of the Japan Pediatric Society   65 ( 1 )   e15460   2023年1月

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記述言語：英語  

DOI： 10.1111/ped.15460

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Ribavirin Treatment for Severe Schizophrenia with Anti-Borna Disease Virus 1 Antibodies 30 Years after Onset. 査読 国際誌

Hidenori Matsunaga, Akio Fukumori, Kohji Mori, Takashi Morihara, Shunsuke Sato, Kyoko Kitauchi, Kanta Yanagida, Kazumi Taguchi, Tomoyuki Honda, Keizo Tomonaga

Case reports in psychiatry   2023   4899364 - 4899364   2023年

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記述言語：英語  

OBJECTIVE: Borna disease virus 1 (BoDV-1) was proven to cause fatal encephalitis in humans in 2018. However, the effects of persistent infections remain unclear. Here, we present the case of a 50-year-old woman with a 30-year history of severe schizophrenia, who was exposed to fleas from stray cats prior to disease onset, suggesting the possibility of zoonosis including BoDV-1 infection. The patient had experienced significant social impairment, thought deterioration, delusions, and hallucinations for more than 20 years. METHOD: A radioligand assay was used to test the patient for IgG and IgM antibodies against BoDV-1 nucleoprotein (N) and phosphoprotein (P). Based on the protocol for hepatitis C, we treated the patient with 400 mg/day ribavirin, which was later increased to 600 mg/day. RESULTS: The serological examination revealed anti-BoDV-1 N IgG. Although only subtle changes were observed over the 24 weeks of treatment, the family noticed that the patient's Cotard delusions had disappeared 7 months after completing the treatment, accompanied by some improvements in the relationship with the family. CONCLUSION: Though definite proof was not obtained, this presumed suppression of BoDV-1 by ribavirin leading to improvements in Cotard syndrome-like symptoms suggests that intractable schizophrenia might be one of the BoDV-1 infection phenotypes. Further studies are needed to clarify the effect of persistent BoDV-1 infections in humans.

DOI： 10.1155/2023/4899364

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Cap Analysis of Gene Expression Clarifies Transcriptomic Divergence Within Monozygotic Twin Pairs. 査読

Hirokazu Katoh, Hiroaki Asai, Keiko Takemoto, Rie Tomizawa, Chika Honda, Mikio Watanabe, Osaka Twin, Researrch Group, Tomoyuki Honda

Twin Research and Human Genetics   1 - 8   2023年

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1017/thg.2023.42

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RSウイルス感染症の全国サーベイランスとGoogle Trendsの相関性に関する検討

宇田 和宏, 萩谷 英大, 頼藤 貴志, 小山 敏広, 茂原 研司, 津下 充, 八代 将登, 本田 知之, 塚原 宏一

日本小児感染症学会総会・学術集会プログラム・抄録集   54回   194 - 194   2022年11月

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記述言語：日本語   出版者・発行元：(一社)日本小児感染症学会  

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Viral Sequences Are Repurposed for Controlling Antiviral Responses as Non-Retroviral Endogenous Viral Elements. 招待 査読

Hirohito Ogawa, Tomoyuki Honda

Acta medica Okayama   76 ( 5 )   503 - 510   2022年10月

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.18926/AMO/64025

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Waning of Anti-SARS-CoV-2 Spike Antibody Levels 100 to 200 Days after the Second Dose of the BNT162b2 Vaccine. 査読 国際誌

Hidenori Matsunaga, Hidefumi Takeuchi, Yuichiro Oba, Satoshi Fujimi, Tomoyuki Honda, Keizo Tomonaga

Vaccines   10 ( 2 )   2022年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Anti-SARS-CoV-2 antibodies of 444 vaccinated hospital employees in Japan were measured 94-109 days and 199-212 days after receiving the second BNT162b2 vaccine dose to evaluate the intensity and duration of antibody response in our own cohort. Among uninfected participants, anti-S antibody levels were greatly decreased 199-212 days after the second vaccination compared to the levels measured 94-109 days after the second vaccination (median levels: 830 AU/mL and 2425 AU/mL, respectively; p < 0.001). The rate of decrease between the two testing periods was lower in infected participants than in uninfected participants (median: 47.7% and 33.9%, respectively; p < 0.001). Anti-S antibody levels were significantly higher in females (median: females, 2546 AU/mL; males, 2041 AU/mL; p = 0.002 during the first test period). The peak body temperature after vaccination was higher in females than in males (median: females, 37.4 °C; males: 37.1 °C; p = 0.044). Older males tended to have lower antibody levels. In conclusion, the duration of the anti-S antibody response to the BNT162b2 vaccine was short-lived, particularly in males. Anti-S antibody levels of 1000 AU/mL or lower according to SARS-CoV-2 IgG II Quant (Abbott) might indicate insufficient prevention against the delta variant, and the majority of participants appeared to have lost their protection 200 days after vaccination.

DOI： 10.3390/vaccines10020177

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Nectin-2 Acts as a Viral Entry Mediated Molecule That Binds to Human Herpesvirus 6B Glycoprotein B 査読

Hirohito Ogawa, Daisuke Fujikura, Hikaru Namba, Nobuko Yamashita, Tomoyuki Honda, Masao Yamada

Viruses   14 ( 1 )   160 - 160   2022年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/v14010160

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「抗ボルナウイルス抗体陽性で難治の精神神経症状をもつ症例に対するリバビリン治療」を行った一例

松永 秀典, 陸 馨仙, 北内 京子, 福本 裕美, 本田 知之, 福森 亮雄, 朝長 啓造

NEUROINFECTION   26 ( 2 )   56 - 56   2021年9月

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記述言語：日本語   出版者・発行元：日本神経感染症学会  

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

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年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 査読

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

Journal of Virology   95 ( 14 )   2021年6月

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掲載種別：研究論文（学術雑誌）   出版者・発行元：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. 査読 国際誌

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年3月

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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. 査読 国際誌

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

Viruses   13 ( 2 )   2021年2月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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A traditional Chinese medicine, maoto, suppresses hepatitis B virus production 査読 国際誌

Md Arifur Rahman, Keiji Ueda, Tomoyuki Honda

Frontiers in Cellular and Infection Microbiology   in press   581345 - 581345   2020年12月

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fcimb.2020.581345

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

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

Scientific Reports   10 ( 1 )   in press   2020年12月

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-020-79197-y

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その他リンク： http://www.nature.com/articles/s41598-020-79197-y

Modeling Borna Disease Virus In Vitro Spread Reveals the Mode of Antiviral Effect Conferred by an Endogenous Bornavirus-Like Element 査読 国際誌

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

Journal of Virology   94 ( 21 )   e01204-20   2020年8月

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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. 査読 国際誌

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年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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. 査読 国際誌

Honda T, Nakayama R, Kawahara Y, Yuge L, Ueda K

Virus Research   276   197821 - 197821   2020年1月

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.virusres.2019.197821

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Relaunching human bornavirus research from severe encephalitis cases with unclear etiology 招待 査読

Honda T

The Lancet Infectious Diseases   in press   2020年1月

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：英語  

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RNA Virus-Based Episomal Vector with a Fail-Safe Switch Facilitating Efficient Genetic Modification and Differentiation of iPSCs. 査読 国際誌

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年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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. 査読 国際誌

Tomoyuki Honda, Keiko Takemoto, Keiji Ueda

International journal of molecular sciences   20 ( 12 )   2875   2019年6月

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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. 査読 国際誌

Nakayama R, Ueno Y, Ueda K, Honda T

Oncogene   38 ( 22 )   4340 - 4351   2019年5月

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41388-019-0726-5

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Profiling of LINE-1-Related Genes in Hepatocellular Carcinoma. 招待 査読

Honda T, Rahman MA

International Journal of Molecular Sciences   20 ( 3 )   645   2019年2月

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担当区分：筆頭著者,　責任著者   記述言語：英語  

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. 査読 国際誌

Da Teng, Shunsuke Obika, Keiji Ueda, Tomoyuki Honda

Frontiers in microbiology   10   2781 - 2781   2019年

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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. 査読 国際誌

Yusuke Yamamoto, Keizo Tomonaga, Tomoyuki Honda

Frontiers in microbiology   10   2485 - 2485   2019年

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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. 査読 国際誌

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

International journal of molecular sciences   19 ( 10 )   2018年10月

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 査読

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

Japanese Journal of Infectious Diseases   71 ( 5 )   338 - 342   2018年9月

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掲載種別：研究論文（学術雑誌）   出版者・発行元：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. 査読 国際誌

Yang Z, Honda T, Ueda K

Virology   522   106 - 121   2018年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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. 査読 国際誌

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

Microbiology and immunology   2018年5月

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 査読

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

Journal of Virology   92 ( 5 )   2018年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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. 査読

Sofuku K, Honda T

Gene Expression and Regulation in Mammalian Cells   67 - 80   2018年

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担当区分：最終著者,　責任著者  

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Importance of Promyelocytic Leukema Protein (PML) for Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication. 査読 国際誌

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

Frontiers in microbiology   9   2324 - 2324   2018年

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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.

DOI： 10.3389/fmicb.2018.02324

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

Tomoyuki Honda

FRONTIERS IN MICROBIOLOGY   8   2537   2017年12月

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担当区分：筆頭著者,　責任著者   記述言語：英語   出版者・発行元：FRONTIERS MEDIA SA  

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.

DOI： 10.3389/fmicb.2017.02537

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

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

VIROLOGY   510   104 - 110   2017年10月

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

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.

DOI： 10.1016/j.virol.2017.07.011

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

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

JAPANESE JOURNAL OF INFECTIOUS DISEASES   70 ( 5 )   599 - 599   2017年9月

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担当区分：筆頭著者,　責任著者   記述言語：英語   出版者・発行元：NATL INST INFECTIOUS DISEASES  

DOI： 10.7883/yoken.JJID.2017.E001

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

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

MICROBIOLOGY AND IMMUNOLOGY   61 ( 9 )   380 - 386   2017年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

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.

DOI： 10.1111/1348-0421.12505

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

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

ANTIVIRAL RESEARCH   143   237 - 245   2017年7月

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

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.

DOI： 10.1016/j.antiviral.2017.04.018

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

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年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MICROBIOLOGY SOC  

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.

DOI： 10.1099/jgv.0.000842

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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 査読

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年6月

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記述言語：日本語   出版者・発行元：(公社)日本精神神経学会  

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

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

JAPANESE JOURNAL OF INFECTIOUS DISEASES   70 ( 2 )   225 - 227   2017年3月

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATL INST INFECTIOUS DISEASES  

DOI： 10.7883/yoken.JJID.2016.277

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

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

JOURNAL OF BIOLOGICAL CHEMISTRY   291 ( 50 )   25789 - 25798   2016年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

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.

DOI： 10.1074/jbc.M116.746396

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Measles virus induces persistent infection by autoregulation of viral replication 査読

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

SCIENTIFIC REPORTS   6   37163   2016年11月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

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.

DOI： 10.1038/srep37163

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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年9月

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記述言語：日本語   出版者・発行元：日本神経感染症学会  

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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 査読

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

MICROBIOLOGY AND IMMUNOLOGY   60 ( 6 )   437 - 441   2016年6月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

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.

DOI： 10.1111/1348-0421.12385

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

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年5月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

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.

DOI： 10.1038/srep25873

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

Tomoyuki Honda

FRONTIERS IN CHEMISTRY   4   21   2016年5月

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担当区分：筆頭著者,　責任著者   記述言語：英語   出版者・発行元：FRONTIERS MEDIA SA  

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.

DOI： 10.3389/fchem.2016.00021

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

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

SCIENTIFIC REPORTS   6   26154   2016年5月

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

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.

DOI： 10.1038/srep26154

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

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年2月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC MICROBIOLOGY  

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.

DOI： 10.1128/JVI.02246-15

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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年

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DOI： 10.2222/jsv.66.39

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

Tomoyuki Honda, Keizo Tomonaga

Mobile Genetic Elements   6 ( 3 )   e1165785   2016年

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担当区分：筆頭著者,　責任著者   記述言語：英語   出版者・発行元：Taylor and Francis Inc.  

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.

DOI： 10.1080/2159256X.2016.1165785

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Possible roles of endogenous RNA virus elements in RNA virus infection. 査読

Honda T, Tomonaga K

Uirusu   66 ( 1 )   39 - 46   2016年

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担当区分：筆頭著者,　責任著者   記述言語：日本語   出版者・発行元：日本ウィルス学会  

DOI： 10.2222/jsv.66.39

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その他リンク： http://search.jamas.or.jp/link/ui/2016323293

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

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

JOURNAL OF GENERAL VIROLOGY   96 ( 11 )   3198 - 3203   2015年10月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC GENERAL MICROBIOLOGY  

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.

DOI： 10.1099/jgv.0.000273

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

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年10月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT  

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.

DOI： 10.1261/rna.052092.115

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

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

CELL REPORTS   12 ( 10 )   1548 - 1554   2015年9月

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CELL PRESS  

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.

DOI： 10.1016/j.celrep.2015.08.007

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IFN-β-inducing, unusual viral RNA species produced by paramyxovirus infection accumulated into distinct cytoplasmic structures in an RNA-type-dependent manner. 査読

Yoshida A, Kawabata R, Honda T, Tomonaga K, Sakaguchi T, Irie T

Frontiers in microbiology   6   804   2015年8月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fmicb.2015.00804

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Borna disease virus possesses an NF-ĸB inhibitory sequence in the nucleoprotein gene. 査読

Makino A, Fujino K, Parrish NF, Honda T, Tomonaga K

Scientific reports   5   8696   2015年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/srep08696

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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年

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Neuropathogenesis of persistent infection with Borna disease virus. 査読

Honda T

Uirusu   65 ( 1 )   145 - 154   2015年

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担当区分：筆頭著者,　責任著者   記述言語：日本語   出版者・発行元：日本ウイルス学会  

ボルナ病ウイルス(Borna disease virus: BDV)は，強い神経指向性を持ち，中枢神経系へ持続感染するマイナス鎖RNAウイルスである．自然感染した動物では，致死性脳炎から軽微な神経症状まで，様々な神経症状を呈する．BDV感染による病原性発現の分子メカニズムについては，未だ不明な点が多い．細胞非傷害性であるBDVの病原性は，必ずしもウイルス量に相関せず，感染細胞の質的変化・機能異常によるものと考えられる．これは多くの細胞傷害性ウイルスの病原性がウイルス量と相関するのと大きく異なる．本稿では，BDV感染による病原性発現機構について，私たちが見出した２つの現象を紹介する．グリア細胞は，BDV Pタンパク質発現により，周辺のIGFシグナルの異常を引き起こし，BDV感染病態を誘導する．一部の感染細胞では，BDV mRNAの逆転写と宿主ゲノムへのインテグレーションが起こる．この挿入配列は，BDVタンパク質のバランス変化，BDVを認識するpiRNA産生，周辺遺伝子の発現変化などを引き起こしうる．BDV感染動物では，これらが複雑に絡み合い，様々な症状を呈しているものと考えられる．

DOI： 10.2222/jsv.65.145

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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年

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記述言語：日本語   出版者・発行元：日本ウイルス学会  

ボルナ病ウイルス(Borna disease virus: BDV)は，強い神経指向性を持ち，中枢神経系へ持続感染するマイナス鎖RNAウイルスである．自然感染した動物では，致死性脳炎から軽微な神経症状まで，様々な神経症状を呈する．BDV感染による病原性発現の分子メカニズムについては，未だ不明な点が多い．細胞非傷害性であるBDVの病原性は，必ずしもウイルス量に相関せず，感染細胞の質的変化・機能異常によるものと考えられる．これは多くの細胞傷害性ウイルスの病原性がウイルス量と相関するのと大きく異なる．本稿では，BDV感染による病原性発現機構について，私たちが見出した２つの現象を紹介する．グリア細胞は，BDV Pタンパク質発現により，周辺のIGFシグナルの異常を引き起こし，BDV感染病態を誘導する．一部の感染細胞では，BDV mRNAの逆転写と宿主ゲノムへのインテグレーションが起こる．この挿入配列は，BDVタンパク質のバランス変化，BDVを認識するpiRNA産生，周辺遺伝子の発現変化などを引き起こしうる．BDV感染動物では，これらが複雑に絡み合い，様々な症状を呈しているものと考えられる．

DOI： 10.2222/jsv.65.145

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

Shohei Kojima, Tomoyuki Honda, Yusuke Matsumoto, Keizo Tomonaga

MICROBIOLOGY AND IMMUNOLOGY   58 ( 11 )   636 - 642   2014年11月

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

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.

DOI： 10.1111/1348-0421.12193

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

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年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATL ACAD SCIENCES  

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.

DOI： 10.1073/pnas.1407046111

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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年12月

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Nucleocytoplasmic Shuttling of Viral Proteins in Borna Disease Virus Infection 査読

Tomoyuki Honda, Keizo Tomonaga

VIRUSES-BASEL   5 ( 8 )   1978 - 1990   2013年8月

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担当区分：筆頭著者,　責任著者   記述言語：英語   出版者・発行元：MDPI AG  

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.

DOI： 10.3390/v5081978

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Host Molecular Chaperones: Cell Surface Receptors for Viruses. 査読

Honda T, Tomonaga K

Heat Shock Proteins   7   293 - 307   2013年

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担当区分：筆頭著者,　責任著者  

DOI： 10.1007/978-94-007-6787-4_19

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Pathogenesis of Encephalitis Caused by Persistent Measles Virus Infection. 査読

Honda T, Yoneda M, Sato H, Kai C

Encephalitis   251 - 262   2013年

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

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

PLOS ONE   7 ( 12 )   e51161   2012年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

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.

DOI： 10.1371/journal.pone.0051161

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Generation of Human Bronchial Epithelial Cell Lines Expressing Inactive Mutants of GALNT3 査読

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

JOURNAL OF VETERINARY MEDICAL SCIENCE   74 ( 11 )   1493 - 1496   2012年11月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC VET SCI  

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.

DOI： 10.1292/jvms.12-0199

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

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年5月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CELL PRESS  

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.

DOI： 10.1016/j.chom.2012.04.009

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

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

MICROBIOLOGY AND IMMUNOLOGY   56 ( 5 )   346 - 349   2012年5月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

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.

DOI： 10.1111/j.1348-0421.2012.00436.x

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Morbillivirus receptors and tropism: multiple pathways for infection 査読

Hiroki Sato, Misako Yoneda, Tomoyuki Honda, Chieko Kai

FRONTIERS IN MICROBIOLOGY   3   75   2012年

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記述言語：英語   出版者・発行元：FRONTIERS RESEARCH FOUNDATION  

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.

DOI： 10.3389/fmicb.2012.00075

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

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

JOURNAL OF VIROLOGY   85 ( 23 )   12170 - 12178   2011年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC MICROBIOLOGY  

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.

DOI： 10.1128/JVI.05554-11

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

Hiroki Sato, Misako Yoneda, Tomoyuki Honda, Chieko Kai

VIRUS RESEARCH   162 ( 1-2 )   63 - 71   2011年12月

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記述言語：英語   出版者・発行元：ELSEVIER SCIENCE BV  

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.

DOI： 10.1016/j.virusres.2011.09.038

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

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年5月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC MICROBIOLOGY  

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.

DOI： 10.1128/JVI.01817-10

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Endogenous non-retroviral RNA virus elements in mammalian genomes 査読

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年1月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

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.

DOI： 10.1038/nature08695

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

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

JOURNAL OF VIROLOGY   83 ( 23 )   12622 - 12625   2009年12月

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC MICROBIOLOGY  

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.

DOI： 10.1128/JVI.01201-09

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

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

MICROBES AND INFECTION   11 ( 3 )   394 - 402   2009年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

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.

DOI： 10.1016/j.micinf.2009.01.006

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

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

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   477 ( 2 )   267 - 278   2008年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

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.

DOI： 10.1016/j.abb.2008.07.013

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Dipole source analysis of temporal slow waves in the elderly 査読

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年

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

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.

DOI： 10.1159/000123116

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

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

JOURNAL OF CELL BIOLOGY   174 ( 1 )   141 - 151   2006年7月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ROCKEFELLER UNIV PRESS  

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.

DOI： 10.1083/jcb.200601089

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

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年2月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

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.

DOI： 10.1016/j.mcn.2005.10.002

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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年

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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年

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

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年8月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ROCKEFELLER UNIV PRESS  

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.

DOI： 10.1083/jcb.200401093

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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 査読

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年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC CELL BIOLOGY  

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.

DOI： 10.1091/mbc.E03-05-0321

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

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

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   306 ( 1 )   104 - 109   2003年6月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

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.

DOI： 10.1016/S0006-291X(03)00919-7

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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 査読

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

GENES TO CELLS   8 ( 5 )   481 - 491   2003年5月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING LTD  

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 査読

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

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   302 ( 1 )   61 - 66   2003年2月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

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.

DOI： 10.1016/S0006-291X(03)00106-2

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

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年1月

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING LTD  

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.

DOI： 10.1046/j.1365-2443.2003.00616.x

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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 査読

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

JOURNAL OF BIOLOGICAL CHEMISTRY   277 ( 52 )   50749 - 50755   2002年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

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.

DOI： 10.1074/jbc.M209846200

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Role of nectin in organization of tight junctions in epithelial cells 査読

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

GENES TO CELLS   7 ( 10 )   1059 - 1072   2002年10月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING LTD  

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.

DOI： 10.1046/j.1365-2443.2002.00578.x

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

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年10月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

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.

DOI： 10.1038/sj.onc.1205875

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

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

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   293 ( 1 )   45 - 49   2002年4月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

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.

DOI： 10.1016/S0006-291X(02)00183-3

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Nectin: an adhesion molecule involved in formation of synapses 査読

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年2月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ROCKEFELLER UNIV PRESS  

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.

DOI： 10.1083/jcb.200103113

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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年

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

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

JOURNAL OF BIOLOGICAL CHEMISTRY   273 ( 12 )   6591 - 6594   1998年3月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

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.

DOI： 10.1074/jbc.273.12.6591

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

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

JOURNAL OF BIOLOGICAL CHEMISTRY   271 ( 43 )   27013 - 27017   1996年10月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

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.

DOI： 10.1074/jbc.271.43.27013

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