Faculty Profiles - OKAMOTO Kuniaki

MISC - OKAMOTO Kuniaki

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Involvement of glycosphingolipids in LPS mediated survival of mature osteoclasts

E Sakai, S Fukumoto, K Nishishita, JP Hu, K Okamoto, Y Kato

JOURNAL OF PHARMACOLOGICAL SCIENCES 100 65P - 65P 2006

カテプシンE欠損マクロファージにおける膜タンパク質の輸送異常

筑波隆幸, 山本晋也, 山本晋也, 柳川三千代, 柳川三千代, 岡元邦彰, 門脇知子, 山本健二

Journal of Oral Biosciences 48 ( Supplement ) 2006

P.gingivalis感染の生活習慣病増悪機序について

門脇知子, 筑波隆幸, 瀧井良祐, 重松直樹, 岡元邦彰, 山本健二

Journal of Oral Biosciences 48 ( Supplement ) 2006

The role of the cathepsin E propeptide in correct folding, maturation and sorting to the endosome

Y Yasuda, T Tsukuba, K Okamoto, T Kadowaki, K Yamamoto

JOURNAL OF BIOCHEMISTRY 138 ( 5 ) 621 - 630 2005.11

Language：English Publisher：OXFORD UNIV PRESS

Cathepsin E (CE) is an endosomal aspartic proteinase of the A1 family that is highly homologous to the lysosomal aspartic proteinase cathepsin D (CD). Newly synthesized CE undergoes several proteolytic processing events to yield mature CE, from which the N-terminal propeptide usually comprising 39 amino acids is removed. To define the role of the propeptide of CE in its biosynthesis and processing, we constructed two fusion proteins using chimeric DNAs encoding the CE propeptide fused to the mature CD tagged with HA at the COOH terminus (termed ED-HA) and encoding the CD propeptide fused to the mature CE (termed DE). Pulse-chase analysis revealed that wild-type CE expressed in human embryonic kidney cells is autoproteolytically processed into mature CE within a 12-h chase, whereas the chimeric DE failed to be converted into mature CE even after a 24-h chase. The DE chimera was nevertheless capable of acid-dependent autoactivation in vitro to yield a catalytically active form, although its specificity constants (k(cat)/K(m)) were considerably high but less (35%) than those of the wild-type CE. By contrast, the chimeric ED-HA expressed in HeLa cells underwent neither processing into a catalytically active enzyme nor acid-dependent autoactivation in vitro. The ED-HA protein was less stable than wt-CD-HA, as determined on pulse-chase analysis and on trypsin digestion. These data indicate that the propeptide of CE is essential for the correct folding, maturation, and targeting of this protein to its final destination.

DOI： 10.1093/jb/mvi159

Identification of a new membrane-associated protein that influences transport/maturation of gingipains and adhesins of Porphyromonas gingivalis

K Sato, E Sakai, PD Veith, M Shoji, Y Kikuchi, H Yukitake, N Ohara, M Naito, K Okamoto, EC Reynolds, K Nakayama

JOURNAL OF BIOLOGICAL CHEMISTRY 280 ( 10 ) 8668 - 8677 2005.3

Language：English Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

The dual membrane envelopes of Gram-negative bacteria provide two barriers of unlike nature that regulate the transport of molecules into and out of organisms. Organisms have developed several systems for transport across the inner and outer membranes. The Gram-negative periodontopathogenic bacterium Porphyromonas gingivalis produces proteinase and adhesin complexes, gingipains/adhesins, on the cell surface and in the extracellular milieu as one of the major virulence factors. Gingipains and/or adhesins are encoded by kgp, rgpA, rgpB, and hagA on the chromosome. In this study, we isolated a P. gingivalis mutant (porT), which showed very weak activities of gingipains in the cell lysates and culture supernatants. Subcellular fractionation and immunoblot analysis demonstrated that precursor forms of gingipains and adhesins were accumulated in the periplasmic space of the porT mutant cells. Peptide mass fingerprinting and N-terminal amino acid sequencing of the precursor proteins and the kgp'-'rgpB chimera gene product in the porT mutant indicated that these proteins lacked the signal peptide regions, consistent with their accumulation in the periplasm. The PorT protein seemed to be membrane-associated and exposed to the periplasmic space, as revealed by subcellular fractionation and immunoblot analysis using anti-PorT antiserum. These results suggest that the membrane-associated protein PorT is essential for transport of the kgp, rgpA, rgpB, and hagA gene products across the outer membrane from the periplasm to the cell surface, where they are processed and matured.

DOI： 10.1074/jbc.M413544200

Alteration of substance P levels in various regions of mouse brain caused by cathepsin E-deficiency

N Shigematsu, T Nishioku, T Tsukuba, T Fukuda, T Yamamoto, T Yamaguchi, S Kohsaka, K Okamoto, Y Okamoto, Y Tanaka, M Himeno, S Higuchi, K Yamamoto

JOURNAL OF PHARMACOLOGICAL SCIENCES 97 72P - 72P 2005

Up-regulation, Enhanced Maturation, and Secretion of Cathepsin E in Mouse Macrophages Treated with Interferon-γ or Lipopolysaccharide

Michiyo Yanagawa, Takayuki Tsukuba, Kuniaki Okamoto, Ryosuke Takii, Yoshihiro Terada, Tomoko Kadowaki, Kenji Yamamoto

journal of oral biosciences 48 ( 3 ) 218 - 225 2005

Language：English

Cathepsin E is an intracellular aspartic proteinase that is predominantly localized in the endosomal compartments of antigen presenting cells including macrophages. Here, we have investigated the expression of cathepsin E in mouse macrophages treated with interferon (IFN)-γ, lipopolysaccharide (LPS), interleukin (IL)-10, and IL-4. The mRNA levels of cathepsin E in macrophages stimulated with IFN-γ and LPS were increased, but conversely, that with IL-10 was decreased. However, upon stimulation with IFN-γ or LPS, the activity levels of cathepsin E in the activated cells were markedly decreased, but those in the culture media were increased. Immunoblot analysis revealed that procathepsin E in the cells was largely converted to the mature form in the cells upon stimulation with IFN-γ. In addition, the extracellular enzyme was reacted with antibodies to mature cathepsin E but not with antibodies for procathepsin E. By contrast, when macrophages were treated with IL-4, cathepsin E production was significantly decreased in both the cell and the medium. These results indicate that, upon stimulation with IFN-γ and LPS, cathepsin E is up-regulated in macrophages, which is accompanied by the enhanced maturation and secretion of the enzyme. Conversely, cathepsin E is down-regulated by treatment with IL-4 and IL-10. © 2006, Japanese Association for Oral Biology. All rights reserved.

DOI： 10.2330/joralbiosci.48.218

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Porphyromonas gingivalisの産生するシステインプロテアーゼ(Kgp)の活性中心の決定

岡元邦彰, HU P J, 坂井詠子, 西下一久, 門脇知子, 山本健二, 中山浩次, 加藤有三

Journal of Oral Biosciences 47 ( Supplement ) 2005

Cathepsin E is important for endosomal/lysosomal systems in macrophages against a bacterial infection

T Tsukuba, M Yanagawa, Y Okamoto, K Okamoto, K Yanamoto

JOURNAL OF PHARMACOLOGICAL SCIENCES 97 78P - 78P 2005

Glycosphingolipids regulate osteoclastgenesis mediated by lipopolysaccharide

E Sakai, S Fukumoto, Y Narita, M Tanaka, M Tachi, H Hotokezaka, K Kanaoka, K Okamoto, Y Kato

JOURNAL OF PHARMACOLOGICAL SCIENCES 97 178P - 178P 2005

Roles of Arg- and Lys-gingipains in coaggregation of Porphyromonas gingivalis: identification of its responsible molecules in translation products of rgpA, kgp, and hagA genes

N Abe, A Baba, R Takii, K Nakayama, A Kamaguchi, Y Shibata, Y Abiko, K Okamoto, T Kadowaki, K Yamamoto

BIOLOGICAL CHEMISTRY 385 ( 11 ) 1041 - 1047 2004.11

Language：English Publisher：WALTER DE GRUYTER & CO

Arg- (Rgp) and Lys-gingipains (Kgp) are two individual cysteine proteinases produced by Porphyromonas gingivalis, an oral anaerobic bacterium, and are implicated as major virulence factors in a wide range of pathologies of adult periodontitis. Coaggregation of this bacterium with other oral bacteria is an initial and critical step in infectious processes, yet the factors and mechanisms responsible for this process remain elusive. Here we show that the initial translation products of the rgpA, kgp and hemagglutinin hagA genes are responsible for coaggregation of P gingivalis and that the proteolytic activity of Rgp and Kgp is indispensable in this process. The rgpA rgpB kgp- and rgpA kgp hagA-deficient triple mutants exhibited no coaggregation activity with Actinomyces viscosus, whereas the kgp-null and rgpA rgpB-deficient double mutants significantly retained this activity. Consistently, the combined action of Rgp- and Kgp-specific inhibitors strongly inhibited the coaggregation activity of the bacterium, although single use of Rgp- or Kgp-specific inhibitor significantly retained this activity. We also demonstrate that the 47- and 43-kDa proteins produced from the translation products of the rgpA, kgp, and hagA genes by proteolytic activity of both Rgp and Kgp are responsible for the coaggregation of P. gingivalis.

DOI： 10.1515/BC.2004.135

Web of Science

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ベルベリンのマウス骨髄細胞からの破骨細胞形成への抑制作用

胡錦萍, 西下一久, 柴田光枝, 坂井詠子, 金岡和博, 吉田一, 岡元邦彰, 加藤有三

Journal of oral biosciences 46 ( 5 ) 463 - 463 2004.9

カテプシンEによる免疫アレルギー性疾患の制御機構

筑波隆幸, 柳川三千代, 甲村恵子, 梯裕恵, 岡元邦彰, 山本健二

Journal of oral biosciences 46 ( 5 ) 474 - 474 2004.9

KIAA0377遺伝子産物の破骨細胞様細胞形成におよぼす影響

西下一久, 石田豊, 東洋一, 岡元邦彰, 加藤有三

Journal of oral biosciences 46 ( 5 ) 465 - 465 2004.9

Laminin alpha 2 is essential for odontoblast differentiation regulating dentin sialoprotein expression

K Yuasa, S Fukumoto, Y Kamasaki, A Yamada, E Fukumoto, K Kanaoka, K Saito, H Harada, E Arikawa-Hirasawa, Y Miyagoe-Suzuki, S Takeda, K Okamoto, Y Kato, T Fujiwara

JOURNAL OF BIOLOGICAL CHEMISTRY 279 ( 11 ) 10286 - 10292 2004.3

Language：English Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Laminin alpha2 is subunit of laminin-2 (alpha2beta1gamma1), which is a major component of the muscle basement membrane. Although the laminin alpha2 chain is expressed in the early stage of dental mesenchyme development and localized in the tooth germ basement membrane, its expression pattern in the late stage of tooth germ development and molecular roles are not clearly understood. We analyzed the role of laminin alpha2 in tooth development by using targeted mice with a disrupted lama2 gene. Laminin alpha2 is expressed in dental mesenchymal cells, especially in odontoblasts and during the maturation stage of ameloblasts, but not in the pre-secretory or secretory stages of ameloblasts. Lama2 mutant mice have thin dentin and a widely opened dentinal tube, as compared with wildtype and heterozygote mice, which is similar to the phenotype of dentinogenesis imperfecta. During dentin formation, the expression of dentin sialoprotein, a marker of odontoblast differentiation, was found to be decreased in odontoblasts from mutant mice. Furthermore, in primary cultures of dental mesenchymal cells, dentin matrix protein, and dentin sialophosphoprotein, mRNA expression was increased in laminin-2 coated dishes but not in those coated with other matrices, fibronectin, or type I collagen. Our results suggest that laminin alpha2 is essential for odontoblast differentiation and regulates the expression of dentin matrix proteins.

DOI： 10.1074/jbc.M310013200

Cathepsin E deficiency and brain functions

N Shigematsu, T Nishioku, T Tsukuba, S Kohsaka, K Okamoto, Y Okamoto, T Yamamoto, M Himeno, K Yamamoto

JOURNAL OF PHARMACOLOGICAL SCIENCES 94 89P - 89P 2004

Glycosphingolipids regulate osteoclastgenesis mediated by receptor activator of NF-kB ligand and lipopolysaccharide

E Sakai, S Fukumoto, H Hotokezaka, E Fukumoto, M Shibata, K Kanaoka, T Iwamoto, K Okamoto, Y Kato

JOURNAL OF PHARMACOLOGICAL SCIENCES 94 184P - 184P 2004

Effect of Pepstatin A in osteoclast

H Yoshida, K Okamoto, M Shibata, E Sakai, K Kanaoka, K Yuasa, A Mizuno, K Nishishita, Y Kato

JOURNAL OF PHARMACOLOGICAL SCIENCES 94 188P - 188P 2004

Association of cathepsin E deficiency with development of atopic dermatitis

T Tsukuba, K Okamoto, Y Okamoto, M Yanagawa, K Kohmura, Y Yasuda, H Uchi, T Nakahara, M Furue, K Nakayama, T Kadowaki, K Yamamoto, KI Nakayama

JOURNAL OF BIOCHEMISTRY 134 ( 6 ) 893 - 902 2003.12

Language：English Publisher：OXFORD UNIV PRESS

Atopic dermatitis (AD) is a pruritic inflammatory skin diseases associated with a family history of atropy. Here we show that mice lacking the endolysosomal. aspartic proteinase cathepsin E spontaneously develop skin lesions similar to those of humans with AD when reared under conventional conditions but not under specific pathogen-free conditions. These mice showed the increase in the ratio of CD4(+)/CD8(+) T cells, the strong polarization of naive T cells to T helper 2 cells, and the systemic accumulation of IL-18 and IL-1beta accompanied by a marked increase in IL-4, IL-5, and IgE. The relative rates of degradation of IL-18 and IL-1beta were significantly lower in cathepsin E-deficient mice than wild-type mice. These results strongly suggest that the development of AD in cathepsin E-deficient mice is initiated by systemic accumulation of IL-18 and IL-1beta, mainly due to their reduced turnover rates. In addition, the reduced expression of cathepsin E was also observed in erythrocytes of both humans with AD and the AD mouse model NC/Nga. Cathepsin E deficiency might thus be responsible for the induction of AD in humans and mice.

DOI： 10.1093/jh/mvg216

ベルベリンによる破骨細胞分化因子(RANKL)細胞内シグナリング抑制効果

胡錦萍, 西下一久, 柴田光枝, 岡元邦彰, 加藤有三

歯科基礎医学会雑誌 45 ( 5 ) 374 - 374 2003.9

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