封入体形成因子p62の代謝と病態発症

• Project/Area Number: 20689009
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• 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)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2009: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000); Fiscal Year 2008: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: オートファジー / p62 / ユビキチン / 神経変性疾患 / Nbr1 / Atg7

Research Abstract

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タンパク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タンパク質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、我々は様々な臓器特異的オートファジー不能マウスを作製・解析し、オートファジー不全が神経変性疾患、糖尿病や肝炎などの重篤な表現系を示すことを明らかにしてきた。さらに、これら病態発症に関わる分子としてオートファジーにて選択的に分解されるp62の同定に成功した。つまり、オートファジーによるp62の代謝不全が病態発症(肝障害)の主因であることを見出した。本年度は、昨年成功したLC3-p62の共結晶構造解析を基盤に選択的オートファジーの分子機序の解析を進めた。また、p62の過剰蓄積が確認されているヒト疾患におけるオートファジーの動態解析を進めている。さらに、我々が作製してきたオートファジー関連遺伝子ノックアウトマウスを用いた共同研究により,多彩なオートファジーの役割が明らかになった。
平成21年度より若手研究Sの研究課題を開始するため、発展的解消として若手研究Aを中止にする。

Research Products

• [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 FNBP 1L in antibacterial autophagy. (2009)
  • Author(s): Huett, A., Ng, A., Cao, Z., Kuballa, P., Komatsu, M., Daly, MJ., Podolsky, DK., *^Xavier RJ.
  • Journal Title: J.Immunol. 182 Pages: 4917-4930
  • 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, AM., *^Czaja, MJ.
  • Journal Title: Nature 458 Pages: 1131-1135
  • Peer Reviewed
• [Journal Article] The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseases. (2009)
  • Author(s): *^Yue, Z., Friedman, L., Komatsu, M., Tanaka, K.
  • Journal Title: Biochim.Biophys.Acta. 1793 Pages: 1496-1507
  • Peer Reviewed
• [Journal Article] Autophagy is essential for mitochondrial clearance in mature T lymphocytes. (2009)
  • Author(s): Pua, HH., Guo, J., Komatsu, M., *^He, YW.
  • Journal Title: J.Immunol. 182 Pages: 4045-4055
  • Peer Reviewed
• [Journal Article] The MAP1-LC3 conjugation system is involved in lipid droplet formation. (2009)
  • Author(s): Shibata, M., Yoshimura, K., Furuya, N., Koike, M., Ueno, T., Komatsu, M., Arai, H., Tanaka, K., *^Kominami, E., Uchiyama,Y.
  • Journal Title: Biochem.Biophys.Res.Commun. 382 Pages: 419-423
  • Peer Reviewed
• [Journal Article] A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. (2009)
  • Author(s): Kirkin, V., Lanark, T., Sou, YS., Bjorkoy, G., Nunn, JL., Braun, 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 compens atory increase of beta cell mass in response to high-fat diet. (2008)
  • Author(s): Ebato, G, 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
• [Presentation] Important roles of autopahgy-specific substrate p62 in environmental stress response. (2009)
  • Author(s): 小松雅明
  • Organizer: 第68回日本癌学会学術総会(シンポジウム)
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-03
• [Presentation] Important roles of autopahgy-specific substrate p62 in environmental stress response. (2009)
  • Author(s): Masaaki Komatsu
  • Organizer: 5^<th> International Symposium on Autophagy
  • Place of Presentation: Otsu, Japan.
  • Year and Date: 2009-09-28
• [Presentation] 選択的オートファジーの破綻に伴う細胞内変動 (2009)
  • Author(s): 小松雅明
  • Organizer: 日本生化学関東支部例会(シンポジウム)
  • Place of Presentation: 筑波
  • Year and Date: 2009-06-20
• [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綻に伴う細胞内変動 (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 wi11 we learn? " (Symposium).
  • Place of Presentation: Tokyoo, 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綻と封入体形成機構 (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/MO/portfolio/pg126.html
• [Remarks]
  • URL: http://www.metabolism.jst.go.jp/2ki/komatsu.html
• [Remarks]
  • URL: http://www.rinshoken.or.jp/MO/portfolio/pg126.html
• [Remarks]
  • URL: http://www.metabolism.jst.go.jp/2ki/komatsu.html