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オートファジーを担うApgシステム(高等動物)

Research Project

Project/Area Number 12146205
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionJuntendo University

Principal Investigator

木南 英紀  順天堂大学, 医学部, 教授 (10035496)

Co-Investigator(Kenkyū-buntansha) 内山 安男  大阪大学, 大学院・医学研究科, 教授 (10049091)
Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥80,500,000 (Direct Cost: ¥80,500,000)
Fiscal Year 2004: ¥19,700,000 (Direct Cost: ¥19,700,000)
Fiscal Year 2003: ¥19,900,000 (Direct Cost: ¥19,900,000)
Fiscal Year 2002: ¥19,600,000 (Direct Cost: ¥19,600,000)
Fiscal Year 2001: ¥21,300,000 (Direct Cost: ¥21,300,000)
Keywordsオートファジー / Atg7 / ノックアウトマウス / 蛋白質分解 / ユビキチン / リソソーム / ヒトAPGホモログ / E1酵素 / E2酵素 / モディファイアータンパク質 / MAP-LC3
Research Abstract

オートファジーはダイナミックな膜動態を伴うリソソームによるタンパク質分解機構で、飢餓条件で著明に誘導される。哺乳類では、細胞の内外の環境変化に速やかに応答して不要な、あるいは障害オルガネラやタンパク質を処理して恒常性を維持するのに働くと想定されている。本研究では、高等動物におけるオートファジーの生理機能、病理機能を明らかにするため、オートファジーに必須な遺伝子群Apgシステム(Atgと統一された)の同定および機能解析を進めてきた。ヒトATG遺伝子群の中、とくに二つのユビキチン類似の蛋白修飾システムであるAtg結合修飾システムを構成する遺伝子群に着目している。今年度は個体レベルでのオートファジーの生理機能、病理機能を明らかにする研究を中心に行った。Atg7はAtg12結合修飾システムおよびLC3結合修飾システムに共通するE1様酵素である。このAtg7のコンディショナルノックアウトマウスを作製した.Atg7は個体、臓器レベルでAtg結合修飾システム、オートファゴソーム形成、絶食によって誘導されるバルクタンパク質やオルガネラの分解に必須であることがわかった。また、Atg7欠損マウスの解析により新生児におけるアミノ酸供給にオートファジーが必須であることも確認された。さらに、Atg7欠損は異常な膜構造体、変形ミトコンドリア出現などの様々な細胞異常やユビキチン陽性の凝集体の蓄積をもたらすことを見いだした。これら一連の結果からオートファジーは栄養・代謝制御や細胞内のタンパク質・オルガネラの浄化作用に重要な役割を果たしていることがわかった。現在、オートファジーのより詳細な代謝・生理学的役割や病態における役割について解析を続けている.また、オートファゴソーム膜からのLC3の離脱にApg4Bが関与すること、オートファゴソームの最終の成熟過程にrab7が関与することなどオートファジーの分子機構についても大きな成果が得られた。

Report

(5 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report

Research Products

(34 results)

All 2004 Other

All Journal Article (6 results) Book (1 results) Publications (27 results)

  • [Journal Article] A novel protein-conjugating system for Ufm1, a ubiquitin-fold modifier.2004

    • Author(s)
      Komatsu M et al.
    • Journal Title

      The EMBO Journal 23・9

      Pages: 1977-1986

    • Related Report
      2004 Annual Research Report
  • [Journal Article] HsAtg4B/HsApg4B/autophagin-1 cleaves the carboxyl termini of three human Atg8 homologues and delipidates microtubule-associated -------2004

    • Author(s)
      Tanida I et al.
    • Journal Title

      The Journal of Biological Chemistry 279・35

      Pages: 36268-36276

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Role for Rab7 in maturation of late autophagic vacuoles.2004

    • Author(s)
      Jager S et al.
    • Journal Title

      Journal of Cell Science 117

      Pages: 4837-4848

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Human light chain 3/MAPILC3B is cleaved at its carboxyl-terminal Met121 to expose Gly120 for lipidation and targeting to ---------2004

    • Author(s)
      Tanida I et al.
    • Journal Title

      The Journal of Biological Chemistry 279・46

      Pages: 47704-47710

    • Related Report
      2004 Annual Research Report
  • [Journal Article] LC3 conjugation system in mammalian autophagy.2004

    • Author(s)
      Tanida I et al.
    • Journal Title

      Int J Biochem Cell Biol. 36・12

      Pages: 2503-2518

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and alpha3 integrin.2004

    • Author(s)
      Reiser J et al.
    • Journal Title

      The Journal of Biological Chemistry 101

      Pages: 151615-15620

    • Related Report
      2004 Annual Research Report
  • [Book] Autophagy(Klionsky D.J., ed.)2004

    • Author(s)
      Ueno T et al.
    • Total Pages
      311
    • Publisher
      Eurekah.Com/Landes Bioscience, U.S.A.
    • Related Report
      2004 Annual Research Report
  • [Publications] Yamazaki-Sato H et al.: "The carboxyl terminal 17 amino acids within Apg7 are essential for Apg8 lipidation, but not for Apg12 conjugation."FEBS Lett.. 551. 71-77 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nemoto T et al.: "The mouse APG10 homologue, an E2-like enzyme for Apg12p conjugation, facilitates MAP-LC3 modification."J Biol Chem.. 278. 39517-39526 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Asanuma K et al.: "MAP-LC3, a promising autophagosomal marker, is processed during the differentiation and recovery of podocytes from PAN nephrosis"FASEB J.. 17(9). 1165-1167 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tanida I et al.: "GATE-16 and GABARAP are authentic modifiers mediated by Apg7 and Apg3."Biochem Biophys Res Commun.. 300(3). 637-644 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Koike M et al.: "Involvement of two different cell death pathways in retinal atrophy of cathepsin D-deficient mice."Mol Cell Neurosci.. 22(2). 146-161 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kim BY et al.: "Identification of mouse Vps 16 and biochemical characterization of mammalian class C Vps complex."Biochem Biophys Res Commun.. 311(3). 577-582 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ueno T, Tanida I, Kominami E.: "Autophagy"Klionsky D.J., ed., Eurekah. com/Landes Bioscience, U.S.A.. 311 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tanida I.et al.: "GATE-16 and GABARAP are authentic modifiers mediated by Apg7 and Apg3"Biochem Biophys Res Commun. 300. 637-644 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanida I.et al.: "Human Apg3p/Aut1p homologue is an authentic E2 enzyme for multiple substrates, GATE-16,GABARAP, and MAP-LC3, and facilitates---"J Biol Chem. 277. 13739-13744 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanida I.et al.: "Mammalian Apg12P, but not the Apg12p Apg5p conjugate, facilitates LC3 processing"Biochem Biophys Res Commun. 296. 1164-1170 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanida I.et al.: "Murine Apg12p has a substrate preference for murine Apg7p over three Apg8p homologs"Biochem Biophys Res Commun. 292. 256-262 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshikawa M.et al.: "CLC-3 deficiency leads to phenotypes similar to human neuronal ceroid lipofuscinosis"Genes Cells. 7. 597-605 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kouroku Y.et al.: "Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation"Hum Mol Genet. 11. 1505-1515 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanida, I., et al: "Human Apg3p/Aut1p homologue is an E2 enzyme for multiple substrates,GATE-16,GABARAP,and MAP-LC3,and facilitates the conjugation of ---"J Biol Chem.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanida, I., et al: "The Human homologue of Saccharomyces cerevisiae Apg7p is a protein-activating enzyme for multiple substrates,human Apg12p,GATE-16,---"J. Biol. Chem.. 276. 1701-1706 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Komatsu, M., et al: "The C-terminal region of an Apg7p/Cvt2p is required for homodimerization and is essential for its E1-activity and E1-E2 complex-formation"J. Biol. Chem.. 276. 9846-9854 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kim, B. Y., et al: "Molecular characterization of mammalian homologues of class C Vps proteins that interact with syntaxin-7"J Biol Chem.. 276. 29393-29402 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakanishi, H. et al: "Involvement of nitric oxide released from microglia-macrophages in pathological changes of cathepsin D-deficient mice"J Neurosci.. 21. 7526-7533 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Furuya, N. at al: "Leupeptin-induced appearance of partial fragment of betaine homocysteine methyltransferase during autophagic maturation in rat hepatocytes"J Biochem. 129. 313-320 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ichimura,Y., et al: "A ubiquitin-like system mediates protein lipidation"Nature. 408. 488-492 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kabeya,Y., et al.: "LC3, a mammalian homolog of yeast Apg8p, is localized in autophagosome membranes after processing"EMBO J.. 19. 5720-5728 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Koike,M., et al: "Cathepsin D Deficiency Induces Lysosomal Storage with Ceroid Lipofuscin in Mouse CNS Neurons"J.Neurosci.. 15. 6898-6906 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Okazaki,N. et al: "Interaction of Unc-51-like kinase and MAP light chain 3 related proteins in the brain : Possible role of vesicular transport in……"Mol.Brain.Res.. 85. 1-12 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tanida,I., et al: "The Human homologue of Saccharomyces cerevisiae Apg7p is a protein-activating enzyme for multiple substrates,……"J.Biol.Chem.. 276. 1701-1706 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Komatsu,M., et al: "The C-terminal region of an Apg7p/Cvt2p is required for homodimerization and is essential for its E1-activity and ……"J.Biol.Chem.. 276(In press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 木南英紀 など: "タンパク質分解-分子機構と細胞機能"シュプリンガー・フェアラーク東京. 236 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 木南英紀 など: "神経難病の分子機構"シュプリンガー・フェアラーク東京. 194 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2001-03-31   Modified: 2018-03-28  

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