凝集体形成分子p62による神経変性疾患封入体形成機構

• Project/Area Number: 20023029
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Metropolitan Organization for Medical Research
• Principal Investigator: 小松 雅明 Tokyo Metropolitan Organization for Medical Research, 東京都臨床医学総合研究所, 副参事研究員 (90356254)
• Co-Investigator(Kenkyū-buntansha): 和栗 聡 福島県立医科大学, 医学部, 教授 (30244908)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥7,600,000 (Direct Cost: ¥7,600,000); Fiscal Year 2009: ¥3,800,000 (Direct Cost: ¥3,800,000); Fiscal Year 2008: ¥3,800,000 (Direct Cost: ¥3,800,000)
• Keywords: オートファジー / p62 / ユビキチン / 凝集体 / 神経変性疾患 / Nbr1 / Atg7

Research Abstract

研究目的 オートファジーは、ダイナミックな膜形成(オートファゴソーム形成)を伴う真核生物に保存された蛋白質分解システムである。酵母などの下等単細胞生物においては、オートファジーは飢餓に応答した自己分解を介したアミノ酸供給による生存戦略が唯一の働きと考えられてきた。一方、申請者らは脳特異的オートファジー不能マウスを作製・解析し、オートフナジー不全がヒト神経変性疾患の特徴的構造体であるユビキチン陽性封入体形成を伴った神経変性疾患を引き起こすことを明らかにした。さらに、封入体形成の責任分子としてオートファジーにて選択的に分解されるユビキチン結合タンパク質p62の同定に成功した。つまり、オートファジー不全よるp62過剰蓄積が、ユビキチン-p62陽性の封入体形成を導くことを見出した。本研究では、封入体形成因子p62の神経変性疾患における病態生理的意義の解明を目指す。
研究結果
今回、我々は、オートファジーの障害がp62の異常な蓄積・凝集化に依存して抗酸化たんぱく質群の遺伝子発現誘導を起こすことを見出した。抗酸化たんぱく質群の遺伝子発現は転写因子Nrf2により正に制御されることが明らかにされているが、我々は、p62がNrf2の分解を制御するユビキチンリガーゼKeap1と直接相互作用することを発見した。さらに、構造学的解析から、p62の結合するKeap1の領城が、Nrf2の結合するKeap1の領域と同じ領域であることを明らかにした。つまり、P62が細胞内に過剰に蓄積した場合、Keap1とNrf2の結合を競合的に阻害し、Nrf2の分解が阻害され、その結果、抗酸化たんぱく質群の遺伝子発現が誘導されるという新しい生体防御の仕組みがあることが判明した。今後、神経変性疾患モデルマウスおよびヒト病態部位でも同様の現象が起こっているか否かを検証する予定である。

Research Products

• [Journal Article] The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through Keap1-inactivation. (2010)
  • Author(s): Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y-s., Ueno, I., Sakamoto, A., Tong, K.I., Kim, M., Nishito, Y., Iemura, SI,, Natsume, T., Ueno, T., Kominami, E., Motohashi, H., Tanaka K., Yamamoto M.
  • Journal Title: Nature Cell Biology 12 Pages: 213-223
  • Peer Reviewed
• [Journal Article] PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. (2010)
  • Author(s): Matsuda, N., Sato, S., Shiba, K., Okatsu, K., Saisho, K., Gautier, C.A., Sou, Y.-s., Saiki, S., Kawajiri, S., Sato, F., Kimura, M., Komatsu, M., Hattori, N., Tanaka, K.
  • Journal Title: J Cell Biol 189 Pages: 211-221
  • Peer Reviewed
• [Journal Article] Physiological significance of selective degradation of p62 by autophagy. (2010)
  • Author(s): Komatsu, M., Ichimura, Y
  • Journal Title: FEBS Letters 584 : 1374-1378 (2010) 584 Pages: 1374-1378
  • Peer Reviewed
• [Journal Article] Novel type of E3 ligase for Ufm1-conjugating system. (2010)
  • Author(s): Tatsumi, K., Sou, Y-s., Tada, N., Nakamura, E., Iemura, SI., Natsume, T., Kang, S-H., Chung, C-H., Kasahara, M., Kominami, E., Tanaka, K., Komatsu, M.
  • Journal Title: J Biol Chem 285 Pages: 5417-5427
  • Peer Reviewed
• [Journal Article] Loss of autophagy in erythroid cells leads to defective removal of mitochondria and severe anemia in vivo. (2010)
  • Author(s): Mortensen, M., Ferguson, DJ., Edelmann, M., Kessler, B., Morten, KJ., Komatsu, M., Simon, AK.
  • Journal Title: Proc Natl Acad Sci USA 107 Pages: 832-837
  • Peer Reviewed
• [Journal Article] Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. (2009)
  • Author(s): Zhang, Y., Goldman, S., Baerga, R., Zhao, Y., Komatsu, M., Jin, S.
  • Journal Title: Proc Natl Acad Sci USA 106 Pages: 19860-19865
  • Peer Reviewed
• [Journal Article] Discovery of Atg5/Atg7-independent alternative macroautophagy. (2009)
  • Author(s): Nishida, Y., Arakawa, S., Fujitani, K., Yamaguchi, H., Mizuta, T., Kanaseki, T., Komatsu, M., Otsu, K., Tsujimoto, Y., Shimizu, S.
  • Journal Title: Nature 461 Pages: 654-658
  • Peer Reviewed
• [Journal Article] A novel hybrid yeast-human network analysis reveals an essential role for FNBP1L in antibacterial autophagy. (2009)
  • Author(s): Huett, A., Ng, A., Cao, Z., Kuballa, P., Komatsu, M., Daly, M.J., Podolsky, D.K., Xavier, R.
  • Journal Title: J Immunol 182 : 4917-4930 (2009) 182 Pages: 4917-4930
  • Peer Reviewed
• [Journal Article] A novel hybrid yeast-human network analysis reveals an essential role for FNBP1L in antibacterial autophagy. (2009)
  • Author(s): Wu, JJ., Quijano, C., Chen, E., Liu, H., Cao, L., Fergusson, MM., Rovira, II., Gutkind, S., Daniels, MP., Komatsu, M., Finkel, T.
  • Journal Title: Aging (Albany NY) 9 Pages: 425-437
  • Peer Reviewed
• [Journal Article] Autophagy regulates lipid metabolism. (2009)
  • Author(s): Singh, R., Kaushik, S., Wang, Y., Xiang,Y., Novak, I., Komatsu, M., Tanaka, K., Cuervo, A-M., Czaja, M.J.
  • Journal Title: Nature 458 : 1131-1135(2009) 458 Pages: 1131-1135
  • Peer Reviewed
• [Journal Article] Autophagy is essential for mitochondrial clearance in mature T lymphocytes. (2009)
  • Author(s): Pua, H.H., Guo, J., Komatsu, M., ^*He, Y.W.
  • Journal Title: J Immunol 182 : 4046-4055 (2009) 182 Pages: 14046-14055
  • Peer Reviewed
• [Journal Article] A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. (2009)
  • Author(s): Kiricin, V., Lamark, T., Sou, YS., Bjorkoy, G., Nunn, JL., Bruun, JA., Shvets, E., McEwan, DG., Clausen, TH., Wild, P., Bilusic, I., Theurillat, JP., Overvatn, A., Ishii, T., Elazar, Z., Komatsu, M., ^*Dikic, I., and ^*Johansen, T.
  • Journal Title: Mol. Cell 33 Pages: 505-516
  • Peer Reviewed
• [Journal Article] Biochemical and morphological detection of inclusion bodies in autophagy-deficient mice. (2009)
  • Author(s): ^*Waguri, S., and Komatsu, M.
  • Journal Title: Methods Enzymol. 452 Pages: 215-226
  • Peer Reviewed
• [Journal Article] The Atg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice. (2008)
  • Author(s): Sou, YS., Waguri, S., Iwata, JI., Ueno, T., Fujimura, T., Hara, T., Sawada, N., Yamada, A., Mizushima, N., Uchiyama, Y., Kominami, E., Tanaka, K., and ^*Komatsu M.
  • Journal Title: Mol. Biol. Cell 19 Pages: 4762-4775
  • Peer Reviewed
• [Journal Article] Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. (2008)
  • Author(s): Saitoh, T., Fujita, N., Jang, MH., Uematsu, S., Yang, BG., Satoh, T., Omori, H., Noda, T., Yamamoto, N., Komatsu, M., Tanaka, K., Kawai, T., Tsujimura, T., Takeuchi, O, Yoshimori, T., and ^*Akira S.
  • Journal Title: Nature 456 Pages: 264-268
  • Peer Reviewed
• [Journal Article] Essential role of macroautophagy in pancreatic β-cell survival and proliferation. (2008)
  • Author(s): Jung, HS., Chung, KW., Kim, JW., Kim, J., Komatsu M., Tanaka, K., Nguyen, YH., Kang, TM., Jeong, YT., Han, MS., Lee, MK., Kim, KW., and ^*Lee, MS.
  • Journal Title: Cell Metab. 4 Pages: 318-324
  • Peer Reviewed
• [Journal Article] Autophagy in pancreatic beta cells is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. (2008)
  • Author(s): Ebato, C, Uchida, T., Arakawa, M., Komatsu M., Ueno, T., Azuma, K., Hirose, T., Tanaka, K., Kominami, E., Kawamori, R., ^*Fujitani, Y., and ^*Watada, H.
  • Journal Title: Cell Metab. 4 Pages: 325-332
  • Peer Reviewed
• [Journal Article] Structural basis for sorting mechanism of p62 in selective autophagy. (2008)
  • Author(s): Ichimura, Y., Kumanomido, T., Sou, YS., Mizushima, T., Ezaki, J., Ueno, T., Kominami, E., Yamane, T., Tanaka, K., and ^*Komatsu, M.
  • Journal Title: J. Biol. Chem. 283 Pages: 22847-22857
  • Peer Reviewed
• [Journal Article] Selective autophagy regulates various cellular functions.
  • Author(s): Komatsu, M.
  • Journal Title: Genes Cells (In press)
  • Peer Reviewed
• [Journal Article] Selective degradation of p62 by autophagy.
  • Author(s): Ichimura, Y., Komatsu, M.
  • Journal Title: Seminars in Immunopathy (In press)
  • Peer Reviewed
• [Presentation] 健康と病態における選択的オートファジーの先駆的研究 (2009)
  • Author(s): 小松雅明
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 神奈川県・横浜市
  • Year and Date: 2009-12-11
• [Presentation] Autophagy -the selectivity and pathophysiology-. (2009)
  • Author(s): 小松雅明
  • Organizer: Seminar, University of Cambridge UK
  • Place of Presentation: Cambridge・UK
  • Year and Date: 2009-10-22
• [Presentation] Important roles of autophagy-specific substrate p62 in environmental stress response. (2009)
  • Author(s): 小松雅明
  • Organizer: EMBO Conference on : Autophagy, Cell Biology, Physiology and Pathology
  • Place of Presentation: Monte Verita Ascona・Switzerland
  • Year and Date: 2009-10-19
• [Presentation] Pathophysiological role of selective autophagy in hepatocellular carcinoma. (2009)
  • Author(s): 小松雅明
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 神奈川県・横浜市
  • Year and Date: 2009-10-03
• [Presentation] Important roles of autophagy-specific substrate p62 in environmental stress response. (2009)
  • Author(s): 小松雅明
  • Organizer: International Symposium on Autophagy
  • Place of Presentation: 滋賀県・大津市
  • Year and Date: 2009-09-28
• [Presentation] Inclusion Body Precipitated by Autophagy-Deficiency. (2009)
  • Author(s): Masaaki Komatsu
  • Organizer: Keystone Symposia Neurodegenerative Diseases : New Molecular Mechanisms (Symposium).
  • Place of Presentation: Keystone, Colorado, USA.
  • Year and Date: 2009-02-17
• [Presentation] Important roles of autopahgy-specific substrate p62 in environmental stress response. (2009)
  • Author(s): Masaaki Komatsu
  • Organizer: Molecular Mechanism of Environmental Response to Food and Oxygen III (Symposium).
  • Place of Presentation: Sendai, Japan.
  • Year and Date: 2009-02-10
• [Presentation] 選択的オートファジーの破錠に伴う細胞内変動 (2008)
  • Author(s): 小松雅明
  • Organizer: BMB2008 (第31回日本分子生物学会、第81回日本生化学会合同年会) シンポジウム
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-12
• [Presentation] Inclusion body in autophagy-deficient mice. (2008)
  • Author(s): Masaaki Komatsu
  • Organizer: The 15th Takeda Science Foundation Symposium on Bioscience "Cell Death : what have we learned and what will we learn? " (Symposium).
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2008-12-01
• [Presentation] Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. (2008)
  • Author(s): 小松雅明
  • Organizer: 第31回日本神経科学会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2008-07-11
• [Presentation] 細胞内分解系オートファジーの破錠と封入体形成機構 (2008)
  • Author(s): 小松雅明
  • Organizer: 第31回日本基礎老化学会シンポジウム (平成20年6月13日) 松本.
  • Place of Presentation: 松本
  • Year and Date: 2008-06-13
• [Remarks]
  • URL: http://www.rinshoken.or.jp/activities/t100221.html
• [Remarks]
  • URL: http://www.jst.go.jp/pr/announce/20100222/index.html
• [Remarks]
  • URL: http://www.rinshoken.or.jp/MO/portfolio/pg126.html
• [Remarks]
  • URL: http://www.metabolism.jst.go.jp/2ki/komatsu.html
• [Patent(Industrial Property Rights)] 肝疾患治療薬 (2010)
  • Inventor(s): 小松雅明、田中啓二、丹羽眞一郎,牧野泰孝、笠間隆志
  • Industrial Property Rights Holder: 財団法人東京都医学研究機構、(株)リンク・ジェノミクス
  • Industrial Property Number: 2010-001892
  • Filing Date: 2010-01-07