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生体防御のメカニズム 超分子システムによる免疫識別の分子機構解明

研究報告コード R990004230
掲載日 2001年2月6日
研究者
  • 田中 啓二
研究者所属機関
  • (財)東京都臨床医学総合研究所
研究機関
  • (財)東京都医学研究機構東京都臨床医学総合研究所
報告名称 生体防御のメカニズム 超分子システムによる免疫識別の分子機構解明
報告概要 自己と非自己を峻別する免疫識別は生体防御戦略の要であり、その分子的基礎は主要組織適合性複合体(MHC)と結合するMHCリガンド(抗原ペプチド)の生成機構である。プロテアソームは200万の巨大な多成分複合体酵素であり、生化学史上に例を見ない超分子システムを構成している。我々は世界に先駆けてプロテアソームの蛋白質構造と遺伝子構造を解明すると共に、γ型インターフェロン等のサイトカインが触媒サブユニット群の分子内置換を誘導して”免疫プロテアソーム”を造成し、内在性抗原のプロセシング酵素として作用することを発見した。本研究ではプロテアソームの高次構造や分子集合機序の解析を通して免疫識別の分子機構を解明し、この超分子システムの免疫始動制御における役割の解明を目指す。特に免疫における「標的」選別のメカニズムを解明し病原体を任意に特定できる「再構成抗原提示システム」を確立すると共に宿主の免疫システムを正常に作動・調節・強化する生体防御システムを構築する。これは”免疫学的非自己”を科学的に解明することである。さらに、プロテアソームの構造と機能の解明は、生体超分子システムの構造-機能研究に大きく影響し、医学生物学領域を含めた生命科学研究全般への波及効果は極めて大きいと予想される。
研究分野
  • 生体系モデル一般
  • 細胞構成体の機能
  • 免疫反応一般
  • 酵素一般
  • 抗原・抗体・補体一般
関連発表論文 (1)Okada, K., Wangpoengtrakul, C., Osawa, T., Toyokuni, S., Tanaka, K., and Uchida, K. (1999) 4-Hydroxyy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress in vivo. Identification of the proteasone as a target molecule. J. Biol. Chem. 274, 23787-23793.
(2)Kawakami, T., Suzuki, T., Baek, S.H., Chung, C.H., Ichiyama, A., Hirano, H., Omata, M., Tanaka, K. (1999) Isolation and characterization of cytosolic and membrane-bound deubiquitinating enzymes from bovine brain. J. Biochem 126, 612-623.
(3)Murakami, Y., Matsufuji, S., Hayashi, S., Tanahashi, N., and Tanaka, K. (1999) ATP-dependent sequestration of ornithine decarboxylase by the 26S proteasome, a process coupled to unfolding, is a prerequisite for the degradation. Mol. Cell. Biol. 19, 7216-7227.
(4)Hiyama, H., Yokoi, M., Matsutani, C., Sugasawa, K., Maekawa, T., Tanaka, K., Hoeijmakers, J.H.J., and Hanaoka, F. (1999) Interaction of hHR23 with S5a: The ubiquitin-like domain of hHR23 mediates interaction with S5a subunit of the 26S proteasome. J. Biol. Chem. 28019-28025.
(5)Suzuki, T., Ichiyama, A., Saitoh, H., Kawakami, T., Omata, M., Chung, C.H., Kimura, M., Shimbara, N., and Tanaka, K. (1999) A new 30 kDa ubiquitin-related SUMO-1 hydrolase from bovine brain. J. Biol. Chem. 274, 31131-31134.
(6)Suzuki, H., Kobayashi. M., Takeuchi, M., Furuichi, K., Chiba, T., and Tanaka. T. (1999) Identification of a novel 300-kDa factor termed IκBαE3-F1 that is required for ubiquitinylation of IκBα. FEBS Lett. 458, 3430348.
(7)Takeuchi, J., Fujimuro, M., Yokosawa, H., Tanaka, K., and Toh-e, A. (1999) Rpn9 is required for efficient assembly of the yeast 26S proteasome. Mol. Cell. Biol. 19, 6575-6584.
(8)Shimbara, N., Ogawa, K., Nakajima, H., Yamasaki, N., Hidaka, Y., Niwa, S., Tanahashi, N., and Tanaka. K. (1998) Contribution of proline residue for efficient production of MHC classI-ligands by proteasomes. J. Biol. Chem., 273, 23062-23071
(9)Osaka, F., Kawasaki, H., Aida, N, Saeki, M., Chiba, T., Kawashima, S., Tanaka, K., and Kato, S. (1998) A new NEDD8-ligating system for cullin-4A. Genes & Dev., 12, 2263-2268
(10)Hendil, K.B., Khan, S., and Tanaka, K. (1998) Simultaneous binding of PA28 and PA700 activators to proteasomes. Biochem. J., 332, 749-754
(11)Oikawa, T., Sasaki, T., Nakamura, M., Shimamura, M., Tanahashi, N., Omura, S., and Tanaka, K. (1998) The proteasome is involved in angiogenesis. Biochem. Biophys. Res. Commun., 246, 243-248
(12)Watanabe, T.K., Saito, A., Suzuki, M., Fujiwara. T., Takahashi, E., Slaughter, C.A., DeMartino, G.N., Hendil, K.B., Chung, C.H., Tanahashi, N., and Tanaka, K. (1998) cDNA cloning and characterization of a human proteasomal modulater subunit p27 (PSMD9). Genomics 50, 241-250
(13)Tanahashi, N., Fujiwara, T., Takahashi, E., Shimbara, N., Chung, C.H., and Tanaka, K. (1998) Chromosomal localization and immunological analysis of a family of human 26S proteasomal ATPases. Biochem. Biophys. Res. Commun., 243, 229-232
(14)Chang, Y.-C., Lee, Y.-S., Tejima, T., Tanaka, K., Omura, S., Heintz, N.H., Mitsui, Y., and Magae, J. (1998) Mdm-2 and bax, downstream mediators of the p53 responsive, are degraded by the ubiqutiin-proteasome pathway. Cell Growth Differ., 9, 79-84
(15)Fujimuro, M., Tanaka, K., Yokosawa, H., and Toh-e, A. (1998) Son1 is a component of the 26S proteasome of the yeast Saccharomyces cerevisiae. FEBS Lett., 423, 149-154
(16)Kohda, K., Ishibashi, T., Shimbara, N., Tanaka, K., Matsuda, Y., and Kasahara, M. (1998) Characterization of the mouse PA28 activator complex gene family: Complete organizations of three memberes genes, and a physical map of the -150-kb region containing the α- and β-subunits genes. J. Immunol., 160, 4923-4935
(17)Yanagawa. Y., Ueda, T., Yamamato, K., Sasaki, T., Tanaka. K., Hashimoto, J., Sato, T., and Nakagawa, H. (1998) Cloning and Sequencing of cDNA encoding a non-ATPase subunit homolog of Arabidopsis thaliana MBP1 from the Oriza sativa 26S proteasome. Plant Biotech., 15, 147-150
(18)Baek, S.U., Park, K.C., Kim., K.I., Yoo, Y.J., Tanaka, K., Baker, R.T., and Chung, C.H. (1998) A novel family of ubiquitin-specific protease in chick skeletal muscle with distinct amino- and carboxyl-terminal extensions. Biochem. J., 334, 677-684
(19)Yoo, S.J., Kim, H.H., Shin, D.H., Lee, C.S., Seong, I.S., Seol, J.H., Shimbara, N., Tanaka, K., and Chung, C.H. (1998) Effects of the Cys mutations on structure and function of the ATP-dependent HslVU protease in Escherchia coli: The Cys287 to Val mutation in HslU uncouples the ATP-dependent proteolysis by HslVU from ATP hydrolysis. J. Biol. Chem., 273, 22929-22935
(20)Taya, S., Yamamoto, T., Kano, K., Kawano, Y., Iwamatsu, A., Tsuchiya, T., Tanaka, K., Kanai, M., Wood, S.A., and Kaibuchi, K. (1998) The Ras target AF-6 is a physiological substrate of the Fam deubiquitinating enzyme. J. Cell Biol., 142, 1053-1062
(21)Wojcik, C., Paweletz, N., Tanaka, K., and Wilk, S. (1998) The functional relationship of proteasome activator (PA28) subunits, α, β, and γ (Ki antigen) in NT2 neuronal precursor cells and HeLa S3 cells. Eur. J. Cell. Biol. 77, 151-160
(22)Hori, T., Kato, S., Saeki, M., DeMartino, G.N., Slaughter, C.A., Takeuchi, J., Toh-e, A., and Tanaka, K. (1998) cDNA cloning and functional analysis of p28 (Nas6p) and p40.5 (Nas7p), two novel regulatory subunits, of the 26S proteasome. Gene, 216, 113-122
(23)Ueda, Y., Wang, M., Ou, B.R., Huang, J., Tanaka, K., Ichihara, A., and Forsberg, N.E. (1998) Evidence for the participation of the proteasome and calpain in early phases of muscle cell differentiation. Int. J. Biochem. Cell Biol., 30, 679-694
(24)Fujiwara, T., Saito, A., Suzuki, M., Shinomiya, H., Suzuki, T., Takahashi, E., Tanigami, A., Ichiyama, A., Chung, C.H., Tanaka, K. (1998) Identification and chromosomal assignment of USP1, a novel gene encoding a human ubiquitin-specific protease. Genomics, 4, 155-158
(25)Fujimuro, M., Takada, H., Saeki, Y., Toh-e, A., Tanaka, K., and Yokosawa, H. (1998) Growth-dependent regulation of the 26S proteasome assembly in the budding yeast Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun., 251, 818-823
(26)Suzuki, H., Chiba, T., Kobayashi, M., Takeuchi, M., Furuichi, K., and Tanaka, K. (1999) In vivo and in vitro recruitment of an IκBα-ubiquitin ligase to IκBα phosphorylated by IKK, leading to ubiquitination. Biochem. Biophys. Res. Commun., 256, 121-126.
(27)Suzuki, H., Chiba, T., Kobayashi, M., Takeuchi, M., Suzuki, Ichiyama, A., Ikenoue, T., Omata, M., Furuichi, K., and Tanaka, K. (1999) IκBα ubiquitination is catalyzed by an SCF-like complex containing Skp1, cullin-1, and two F-box/WD40-repeat proteins β TrCP1 and β TrCP2. Biochem. Biophys. Res. Commun., 256, 127-132.
(28)Furukawa, H., Murata, S., Yabe, T., Shimbara, N., Naoto, K., Kashiwase, K., Watanabe, K., Ishikawa, Y., Akaza, T., Tadokoro, K., Tohma, S., Inoue, T., Tokunaga, K., Yamamoto, K., Tanaka, K., and Juji, T. (1999) Splice acceptor site mutation of the TAP1 gene in HLA class I deficiency. J. Clin. Inv., 103, 755-758
(29)Mugita, N., Honda, Y., Nakamura, H., Fujiwara, T. Tnakak K., Omura, S., Shimbara N., Ogawa, M., Saya, H., and Nako, M. (1999) The involvement of proteasome in miogeneic differentiation of murine myocytes and human rhabdomyosarcoma cells. Int. J. Mol. Med. 3, 127-137.
(30)Urano, T., Yashiroda, H., Muraoka, M., Tanaka, K., Hosoi, T., Inoue, S., Ouchi, Y., Tanaka, K., and Toyoshima, T. (1999) p57Kip2 is degraded through the proteasome in osteoblasts stimulated to proliferation by transforming growth factor β1. J. Biol. Chem. 274, 12197-12200.
(31)Suzuki, M., Fujiwara, T., Tanigami, A., Ikenoue, T., Omata, M., Chiba, T., and Tanaka, K. (1999) The TCP1 gene encoding a human F-box/WD40 repeat protein map to chromosome 10q24-q25 by fluorescence in situ hybridization. Genomics 58, 104-105.
(32)Combaret, L., Ralliere, C., Taillandier, D., Tanaka, K., and Attaix, D. (1999) Manipulation of the ubiquitin-proteasome pathway in cachexia: pentoxifylline suppresses the activation of 20S and 26S proteasomes in muscles from tumor-bearing rats. Mol. Biol. Rep. 26, 95-101.
(33)Katagiri, K., Yokosawa, H., Kinashi, T., Kawashima, S., Irie, S., Tanaka, K., and Katagiri, T. (1998) Ubiquitin-proteasome system is involved in the induction of LEF-1/ICAM-1-dependent adhesion of HL-60 cells. J. Leucocyte Biol. 65, 778-785.
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研究制度
  • 戦略的基礎研究推進事業、研究領域「生体防御のメカニズム」研究代表者 田中 啓二((財)東京都臨床医学総合研究所)/科学技術振興事業団
研究報告資料
  • 田中 啓二. 生体防御のメカニズム 超分子システムによる免疫識別の分子機構解明. 戦略的基礎研究推進事業 平成10年度 研究年報,1999. p.170 - 177.

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