オートファジーアクセサリー分子群の遺伝学的機能解析

• Project Area: Proteolysis in the Regulation of Biological Processes
• Project/Area Number: 21025041
• 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 (財)東京都医学総合研究所, 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): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥6,700,000 (Direct Cost: ¥6,700,000); Fiscal Year 2010: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2009: ¥3,400,000 (Direct Cost: ¥3,400,000)
• Keywords: オートフジー / p62 / Keap1 / Nrf2 / 癌 / 凝集体 / ユビキチン / オートファジー / Nbr1 / Alfy

Research Abstract

研究目的
これまでオートファジーは、自己分解によるアミノ酸供給が主な役割であり、実際、栄養飢餓などで激しく誘導されることが知られていた。一方、マウス遺伝学を駆使した我々の動物オートファジーの発生工学的研究から、恒常的に起こっているオートファジーの積極的な特異的タンパク質の処理機構が生体の恒常性維持・管理に重要であり、その破綻が様々なヒト疾病の発症原因となることが判明した。オートファジーの減弱による病態発症機構は不明であったが、ごく最近、我々は、そのプロセスにおいて中心的な役割を担っている分子群としてp62、Alfy、Nbr1の同定に成功した。この分子群は高等動物にのみ存在し、オートファゴソーム局在タンパク質LC3との相互作用を介してオートファジーによりその存在量が規定される。興味深いことに、これらの分子はユビキチン結合能を持ち、神経変性疾患、肝臓病、癌で確認されるユビキチン陽性封入体の構成成分でもある。本研究ではp62、Alfy、Nbr1(オートファジーアクセサリー分子群と命名)の個体レベルの研究を推進する。
研究成果
研究期間内に、Nbr1条件付きノックアウト、p62条件付きノックアウト、GFP融合p62ノックインマウス、p62変異体ノックインマウス、Alfy条件付きノックアウトの作成を終了した。これらマウスを基に選択的オートファジーの病態生理的意義の一端を明らかにした。

Research Products

• [Journal Article] Autophagy-deficient mice develop multiple liver tumors (2011)
  • Author(s): Takamura, et al.
  • Journal Title: Genes Dev. Volume: 25 Pages: 795-800
  • Peer Reviewed
• [Journal Article] Persistent activation of Nrf2 in hepatocellular carcinoma cells (2011)
  • Author(s): Inami, et al.
  • Journal Title: J.Cell Biol. Volume: 193 Pages: 275-284
  • Peer Reviewed
• [Journal Article] Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway : a potential role for protein aggregates in autophagic substrate selection (2010)
  • Author(s): Riley, et al.
  • Journal Title: J.Cell Biol. Volume: 191 Pages: 537-552
  • Peer Reviewed
• [Journal Article] Selective degradation of p62 by autophagy (2010)
  • Author(s): Ichimura, Komatsu
  • Journal Title: Semin.Immunopathol. Volume: 32 Pages: 431-436
  • Peer Reviewed
• [Journal Article] Selective autophagy regulates various cellular functions (2010)
  • Author(s): Komatsu, Ichimura
  • Journal Title: Genes Cells Volume: 15 Pages: 923-933
  • Peer Reviewed
• [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] 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] Selective autophagy regulates various cellular functions (2010)
  • Author(s): Komatsu M
  • Organizer: Pacifichem 2010(Symposium)
  • Place of Presentation: Honolulu USA(招待講演)
  • Year and Date: 2010-12-19
• [Presentation] Pathophysloglcal role of selective autophagy (2010)
  • Author(s): 小松雅明
  • Organizer: 第69回BMB2010(シンポジウム)
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-08
• [Presentation] The tumorigenesis in autophagy-deficient livers (2010)
  • Author(s): 小松雅明
  • Organizer: 第69回日本癌学会学術総会(モーニングレクチャー)
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-24
• [Presentation] Pathophysiological roles of autophagy in mouse liver (2010)
  • Author(s): Komatsu M
  • Organizer: 17^<th> IMHCVRV (Plenary Lecture)
  • Place of Presentation: Yokohama, Japan(招待講演)
  • Year and Date: 2010-09-10
• [Presentation] The regulation of stress-response system by autophagy-specific substrate, p62, and its pathophysiological role in hepatocellular carcinoma (2010)
  • Author(s): Komatsu M
  • Organizer: 30^<th> SAPPORO INTERNATIONAL CANCER SYMPOSIUM MEMBRANE TRAFFIC AND CANCER
  • Place of Presentation: Sapporo, Japan(招待講演)
  • Year and Date: 2010-06-29
• [Presentation] Regulation of Nrf2 by an autophagy-specific substrate, p62 (2010)
  • Author(s): Komatsu M
  • Organizer: 4^<th> Gordon Research Conference, Autophagy in Stress, Development & Diseases
  • Place of Presentation: Barga, Italy(招待講演)
  • Year and Date: 2010-04-27
• [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 Uerita 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
• [Remarks]
  • URL: http://www.igakuken.or.jp/
• [Remarks]
  • URL: http://www.rinshoken.or.JP/activities/t100221.html
• [Remarks]
  • URL: http://www.jst.go.jp/pr/announce/20100222/index.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