Analyses of Molecular Assembly and Diversity of Proteasomes

2009 Fiscal Year Final Research Report

• Project/Area Number: 17002019
• Research Category: Grant-in-Aid for Specially Promoted Research
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Metropolitan Organization for Medical Research
• Principal Investigator: TANAKA Keiji Tokyo Metropolitan Organization for Medical Research, 東京都臨床医学総合研究所, 参事研究員 (10108871)
• Co-Investigator(Kenkyū-buntansha): MURATA Shigeo 東京大学, 大学院・薬学系研究科, 教授 (20344070)
• Project Period (FY): 2005 – 2009
• Keywords: ユビキチン / プロテアソーム / オートファジー / 蛋白質分解 / 分子集合 / 分子多様性 / ガン / 神経変性疾患

Research Abstract

The proteasome is an unusually large cellular apparatus that selectively degrades unnecessary proteins, which must be eliminated from the cells. We defined the molecular mechanisms underling proteasome assembly by the findings of a set of proteasome-dedicated molecular chaperones that assist the correct formation of the proteasome. In addition, we established the new concept on the diversity of the proteasome. Previously, we discovered the "immunoproteasome", which emphasized the specialized functions in immune responses. Lately, we also identified another unique "thymoproteasome", which is expressed exclusively in the thymus. We found that thymoproteasome-deficient mice displayed defective thymic development of CD8+T cells, suggesting a key role for thymoproteasome in the development of the MHC class I-restricted CD8+T cell repertoire during thymic positive selection.

Research Products

• [Journal Article] An inhibitor of deubiquitinating enzyme regulates ubiquitin homeostasis. (2009)
  • Author(s): Kimura, Y., Yashiroda, H., Kudo, T., Koitabashi, S., Murata, S., Kakizuka, A., Tanaka, K.
  • Journal Title: Cell 137 Pages: 549-559
• [Journal Article] Multiple proteasome-interacting proteins assist the assembly of the yeast 19S regulatory particle. (2009)
  • Author(s): Saeki, Y., Toh-e, A., Kudo, T., Kawamura, H., Tanaka, K.
  • Journal Title: Cell 137 Pages: 900-913
• [Journal Article] Assembly pathway of the mammalian proteasome base subcomplex is mediated by multiple specific chaperones. (2009)
  • Author(s): Kaneko, T., Hamazaki, J., Iemura, S., Sasaki, K., Furuyama, K., Natsume, T., Tanaka, K., Murata, S.
  • Journal Title: Cell 137 Pages: 914-925
• [Journal Article] Lysine 63-linked polyubiquitin chain may serve as a targeting signal for the 26S proteasome. (2009)
  • Author(s): Saeki, Y., Kudo, T., Sone, T., Kikuchi, Y., Yokosawa, H., Toh-e, A., Tanaka, K.
  • Journal Title: EMBO J 28 Pages: 359-371
• [Journal Article] Molecular mechanisms of proteasome assembly. (2009)
  • Author(s): Murata, S., Yashiroda, H., Tanaka, K.
  • Journal Title: Nat Rev Mol Cell Biol 10 Pages: 104-115
• [Journal Article] The proteasome: Overview of structure and functions. (2009)
  • Author(s): Tanaka, K.
  • Journal Title: Proc Jpn Acad Ser B85 Pages: 12-36
• [Journal Article] Crystal structure of a chaperone complex that contributes to the assembly of yeast 20S proteasomes. (2008)
  • Author(s): Yashiroda, H., Mizushima, T., Okamoto, K., Kameyama, T., Hayashi, H., Kishimoto, T., Kasahara, M., Kurimoto, E., Sakata, E., Suzuki, A., Hirano, Y., Murata, S., Kato, K., Yamane, T., Tanaka, K.
  • Journal Title: Nat Struct Mol Biol 15 Pages: 228-236
• [Journal Article] -ring assembly pathway of the mammalian 20S proteasome. (2008)
  • Author(s): Hirano, Y., Kaneko, T., Okamoto, K., Bai, M., Yashiroda, H., Furuyama, K., Kato, K., Tanaka, K., Murata, S.
  • Journal Title: EMBO J 27 Pages: 2204-2213
• [Journal Article] Mammalian 26S proteasomes remain intact during protein degradation. (2008)
  • Author(s): Kriegenburg, F., Seeger, M., Saeki, Y., Tanaka, K., Lauridsen, A-M.B., Hartmann-Petersen, R., Hendil, K.B.
  • Journal Title: Cell 135 Pages: 355-365
• [Journal Article] Thymoproteasome: probable role in generating positively selecting peptides. (2008)
  • Author(s): Murata, S., Takahama, Y., Tanaka, K.
  • Journal Title: Curr Opini Immunol 20 Pages: 192-196
• [Journal Article] Cell biology: two hands for degradation. (2008)
  • Author(s): Saeki, Y., Tanaka, K.
  • Journal Title: Nature 453 Pages: 460-461
• [Journal Article] Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. (2007)
  • Author(s): Komatsu, M., Waguri, S., Koike, M., Sou, Y., Ueno, T., Hara, T., Mizushima, N., Iwata, J., Ezaki, J., Murata, S., Hamazaki, J., Nishito, Y., Iemura, S., Natsume, N., Yanagawa, T., Uwayama, J., Warabi, E., Yoshida, H., Ishii, T., Kobayashi, A., Yamamoto, M., Yue, Z., Uchiyama, Y., Kominami, E., Tanaka, K.
  • Journal Title: Cell 131 Pages: 1149-1163
• [Journal Article] Regulation of CD8+ T cell development by thymus-specific proteasomes. (2007)
  • Author(s): Murata, S., Sasaki, K., Kishimoto, T., Niwa, S., Hayashi, H., Takahama, Y., Tanaka, K.
  • Journal Title: Science 316 Pages: 1349-1353
• [Journal Article] Structural basis for selection of glycosylated substrate by SCFFbs1 ubiquitin ligase. (2007)
  • Author(s): Mizushima, T., Yoshida, Y., Kumanomidou, T., Hasegawa, Y., Suzuki, A., Yamane, T., Tanaka, K.
  • Journal Title: Proc Natl Acad Sci USA 104 Pages: 5777-5781
• [Journal Article] Unlocking the proteasome door. (2007)
  • Author(s): Saeki, Y, Tanaka, K.
  • Journal Title: Mol Cell 27 Pages: 865-867
• [Journal Article] Cooperation of multiple chaperones required for the assembly of mammalian 20S proteasomes. (2006)
  • Author(s): Hirano, Y., Hayashi, H., Iemura, S., Hendil, K.B., Niwa, S., Kishimoto, T., Natsume, T., Kasahara, M., Tanaka, K., Murata, S.
  • Journal Title: Mol Cell 24 Pages: 977-984
• [Journal Article] A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomes. (2006)
  • Author(s): Hamazaki, J., Iemura, S., Natsume, T., Yashiroda, H., Tanaka, K., Murata, S.
  • Journal Title: EMBO J. 25 Pages: 4524-4536
• [Journal Article] Loss of autophagy in the central nervous system causes neurodegeneration. (2006)
  • Author(s): Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., Tanaka, K.
  • Journal Title: Nature 441 Pages: 880-884
• [Journal Article] A heterodimeric complex that promotes the assembly of mammalian 20S proteasomes (2005)
  • Author(s): Hirano, Y., Hendil, K.B., Yashiroda, H., Iemura, S., Nagane, R., Hioki, Y., Natsume, T., Tanaka, K., Murata, S.
  • Journal Title: Nature 437 Pages: 1381-1385
• [Journal Article] Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. (2005)
  • Author(s): Komatsu, M., Waguri, S., Ueno, T., Murata, S., Tanida, I., Ezaki, E., Mizushima, N., Ohsumi, Y., Uchiyama, Y., Kominami, E., Tanaka, K., Chiba, T.
  • Journal Title: J. Cell Biol 169 Pages: 425-434
• [Presentation] Unexpected encounter with immunity during my proteasome study. (2008)
  • Author(s): Keiji Tanaka
  • Organizer: Japan-German Immunology Seminar 2008:Immune Regulation in Health and Disease.
  • Place of Presentation: Fukuoka, Japan.
  • Year and Date: 20081103-20081106
• [Presentation] Protein Degradation and Neuro-degenerative Diseases. (2008)
  • Author(s): 田中啓二
  • Organizer: Neuroscience 2008第31回日本神経科学大会. 特別講演。
  • Place of Presentation: 東京フォーラム)東京.
  • Year and Date: 2008-07-10
• [Presentation] The Novel Thymoproteasome Regulates Development of CD8+ T Cells. (2008)
  • Author(s): Keiji Tanaka
  • Organizer: 33rd FEBS Congress & 11th IUBMB Conference(Symposium on the ubiquitin-proteasome system)Peace and Friendship Stadium
  • Place of Presentation: Athens, Greece.
  • Year and Date: 2008-06-30
• [Presentation] プロテアソームの分子集合機構の解明・どのように巨大で複雑な複合体は形成されるか?ターゲット蛋白研究プログラムシンポジウム(19年度文部科学省) (2008)
  • Author(s): 田中啓二
  • Organizer: 東京国際フォーラム
  • Place of Presentation: 東京
  • Year and Date: 2008-02-12
• [Book] 「分子細胞生物学辞典」:免疫プロテアソーム・ハイブリッドプロテアソーム (2008)
  • Author(s): 田中啓二
  • Total Pages: 685,903
  • Publisher: 東京化学同人
• [Book] プロテアソーム:キーワード:蛋白質の一生「蛋白質核酸酵素」増刊号 (2008)
  • Author(s): 田中啓二
  • Total Pages: 995-998
  • Publisher: 共立出版
• [Book] 蛋白質の寿命:蛋白質の事典 (2008)
  • Author(s): 田中啓二
  • Total Pages: 583-589
  • Publisher: 朝倉書店
• [Book] ユビキチンと神経変性:臨床神経科学(Clinical Neuroscience) (2008)
  • Author(s): 田中啓二
  • Total Pages: 1306-1307
  • Publisher: 中外医学社
• [Book] プロテアソームの新しいユビキチンレセプター. 細胞工学 (2008)
  • Author(s): 佐伯泰、田中啓二
  • Total Pages: 902-903
  • Publisher: 学研メディカル秀潤社
• [Book] ユビキチン・プロテアソーム・オートファジー:免疫の事典
  • Author(s): 田中啓二
  • Publisher: 朝倉書店(印刷中)
• [Book] 巨大で複雑な蛋白質分解装置の動態と作動機構「構造プロテオミクスの新時代:医薬の分子設計と構造生物学の融合」蛋白質核酸酵素増刊号
  • Author(s): 水島恒裕・田中啓二
  • Total Pages: 1670-1675
  • Publisher: 共立出版
• [Remarks] 研究代表者:田中啓
  • URL: http://www.rinshoken.or.jp/
• [Remarks] 研究分担者:村田茂穂
  • URL: http://www.f.u-tokyo.ac.jp/