オートファジー発がん抑制説の再検証

• Project/Area Number: 20657037
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Cell biology
• Research Institution: Osaka University
• Principal Investigator: 吉森 保 Osaka University, 微生物病研究所, 教授 (60191649)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2009: ¥1,900,000 (Direct Cost: ¥1,900,000); Fiscal Year 2008: ¥1,400,000 (Direct Cost: ¥1,400,000)
• Keywords: オートファジー / 発がん抑制 / Beclin1 / Rubicon / Atg14L / PI3キナーゼ複合体 / Rab7 / エンドサイトーシス経路 / タンパク質複合体 / エンドソーム

Research Abstract

オートファジーは、真核生物に普遍的に存在する細胞内大規模分解システムである。細胞成分の代謝回転、飢餓時の栄養源確保という基本機能に加え、免疫や発生・分化などにも関わり極めて多機能であることが最近明らかとなってきた。機能の一つとして発がん抑制が言われている。それはオートファジーに必須のタンパク質Beclin1のヘテロKOマウスで自然発生がんが多発すること等が根拠になっている。しかし我々は、Beclin1が2種類の複合体を形成しその一方はオートファジー以外の機能を持つ可能性を見出した。本研究では、このBeclin1複合体の詳細な解析を通して、Beclin1の発がん抑制作用が真にオートファジーを介して行われているのか否かを検証する。本年度は以下の成果を得た。
1.Beclin1に結合するタンパク質として我々が同定した新規タンパク質のRubiconが、エンドサイトーシス経路後期に働くメンブレントラフィック制御因子のrab7との結合を介して、エンドサイトーシス経路後期過程とオートファゴソーム・リソソーム融合の両方を負に制御することを見出した。Rubiconの機能には、rab7と同時にbeclin1を含むPI3キナーゼ複合体と結合している必要があることも判った。
2.Beclin1に相互排除的に結合するAtg14LとRubiconについて、各々コンディショナルKOマウスの作成に成功した。このマウスを用いて個体レベルで発がん抑制について検証することが可能になった。

Research Products

• [Journal Article] Artificial induction of autophagy around polystyrene beads in nonphag ocytic cells. (2010)
  • Author(s): Kobayashi S, Kojidani T, Osakada H, Yamamoto A, Yoshimori T, Hiraoka Y, Haraguchi T^*.
  • Journal Title: Autophagy. 6 Pages: 36-45
  • Peer Reviewed
• [Journal Article] Modulation of local PtdIns3P levels by the PI phosphatase MTMR3 regulates constitutive autophagy. (2010)
  • Author(s): Taguchi-Atarashi N, Hamasaki M, Matsunaga K, Omori H, Ktistakis NT, Yoshimori T, Noda T^*.
  • Journal Title: Traffic. 11(4) Pages: 468-478
  • Peer Reviewed
• [Journal Article] Combinational Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor Proteins VAMP8 and Vtilb Mediate Fusion of Antimicrobial and Canonical Autophagosomes with Lysosomes. (2010)
  • Author(s): Furuta N, Fujita N, Noda T, Yoshimori T, Amano A^*.
  • Journal Title: Mol Biol Cell. 21 Pages: 1001-1010
  • Peer Reviewed
• [Journal Article] Autophagosome can support Yersinia pseudotuberculosis replication in macrophages. (2010)
  • Author(s): Moreau K, Lacas-Gervais S, Fujita N, Sebbane F, Yoshimori T, Simonet M, Lafont F^*.
  • Journal Title: Cell Microbiol. (Feb 23.[Epub ahead of print])
  • Peer Reviewed
• [Journal Article] Two Beclin-1 binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. (2009)
  • Author(s): Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Maejima I, Shirahama-Noda K, Ichimura I, Isobe T, Akira S, Noda T, Yoshimori T^*.
  • Journal Title: Nature Cell Biol. 11 Pages: 385-396
  • Peer Reviewed
• [Journal Article] Autophagic Elimination of Misfolded Procollagen Aggregates in the Endoplasmic Reticulum as a Means of Cell Protection. (2009)
  • Author(s): Ishida Y, Yamamoto A, Kitamura A, Lamande, S, Yoshimori T, Bateman J, Kubota H, Nagata K^*.
  • Journal Title: Mol Biol Cell. 20 Pages: 2744-2754
  • Peer Reviewed
• [Journal Article] Differencial involvement of ATG16LI in Crohn's disease and canonic al autophagy : analysis of the organization of the ATG16LI complex in fibroblasts. (2009)
  • Author(s): Fujita N, Saitoh T.Kageyamas, S, Akira S, Noda T, Yoshimori T^*
  • Journal Title: J Biol Chem. 284 Pages: 32602-32609
  • Peer Reviewed
• [Journal Article] Cochaperone activity of hunman butyrate-induced transcript I facilitates hepatitis C virus replication through an Hsp90-dependent pathway. (2009)
  • Author(s): Taguwa S, Kambara H, Omori H, Tani H, Abe T, Mori Y, Suzuki T, Yoshimori T, Moriishi K, Matsuura Y^*
  • Journal Title: J Virol. 83 Pages: 10427-10436
  • Peer Reviewed
• [Journal Article] Porphyromonas gingivalis outer membrane vesicles enter human epithelial cells via an endocytic pathway and are sorted to Iysosomal comp artments. (2009)
  • Author(s): Furuta N, Tsuda K, Omori H, Yoshimori T, Yoshimura F, Amano A^*.
  • Journal Title: Infect Immun. 77 Pages: 4187-4196
  • Peer Reviewed
• [Journal Article] The Stent-Eluting Drugs Sirolimus and Paclitaxel Suppress Healing of the Endothelium by Induction of Autophagy. (2009)
  • Author(s): Hayashi SI, Yamamoto A, You F, Yamashita K, Ikegame Y, Tawada M, Yoshimori T, Shimizu S, Nakashima S^*.
  • Journal Title: Am J Pathol. 175 Pages: 2226-2234
  • Peer Reviewed
• [Journal Article] A subdomain of the endoplasmic reticulum forms a cradle for autoph agosome formation. (2009)
  • Author(s): Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T^*, Yamamoto A^*.
  • Journal Title: Nat Cell Biol. 11 Pages: 1433-1437
  • Peer Reviewed
• [Journal Article] Atg^9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. (2009)
  • Author(s): Saitoh T, Fujita N, Hayashi T, Takahara K, Satoh T, Lee H, Matsunaga K, Kageyama S, Omori H, Noda T, Yamamoto N, Kawai T, Ishii K, Takeuchi O, Yoshimori T, Akira S.
  • Journal Title: Proc Natl Acad Sci USA. 106(49) Pages: 20842-20846
  • Peer Reviewed
• [Journal Article] An initial step of GAS-containing autophagosome-like vacuoles formation requires Rab7. (2009)
  • Author(s): Yamaguchi H, Nakagawa I, Yamamoto A, Amano A, Noda T, Yoshimori T^*.
  • Journal Title: PLoS Pathog. 5(e1000670.doi : 10.1371/journal.ppat.1000670)
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): Yoshimori T, Amano A.
  • Journal Title: Curr Top Microbiol Immunol.335(Springer) Pages: 217-226
• [Journal Article] Effect of Helicobacter pylori's vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells. (2009)
  • Author(s): Terebiznik MR, Raju D, Vazquez CL, Torbricki K, Kulkami R, Blanke SR, Yoshimori I, Colombo MI, Jones NL.
  • Journal Title: Autophagy. Apr 19:5(3)(Epub ahead of print)
  • Peer Reviewed
• [Journal Article] The Atg16L Complex Specifies the Site of LC3 Lipidation for Membrane Biogenesis in Autophagy. (2008)
  • Author(s): Fujita N, Itoh T, Fukuda M, Noda T, Yoshimori T.
  • Journal Title: Mol Biol Cell. 19 Pages: 2092-2100
  • Peer Reviewed
• [Journal Article] Dynein-dependent Movement of Autophagosomes Mediates Efficient Encounters with Lysosomes. (2008)
  • Author(s): Kimura S, Noda T, Yoshimori T.
  • Journal Title: Cell Struct Funct. 33 Pages: 109-122
  • NAID: 130004137532
  • Peer Reviewed
• [Journal Article] Functional Analysis of α5β1 Integrin and Lipid Rafts in Invasion of Epithelial Cells by Porphyromonas gingivalis using Fluorescent Beads Coatedwith Bacterial Membrane Vesicle. (2008)
  • Author(s): Tsuda K, Furuta N, Inaba H, Kawai s, Hanada K, Yoshimori I, Amano A.
  • Journal Title: Cell Struct Funct. 33 Pages: 123-132
  • Peer Reviewed
• [Journal Article] Golgi-resident small GTPase Rab33B interacts with Atg16L and modulates autophagosome formation. (2008)
  • Author(s): Itoh T, Fujita N, Kanno E, Yamamoto A, Yoshimori T, Fukuda M.
  • Journal Title: Mol Biol Cell. 19 Pages: 2916-2925
  • Peer Reviewed
• [Journal Article] Ubc4/5 and c-Cbl Continue to Ubiquitinate EGF Receptor after Intemalization to Facilitate Polyubiquitination and Degradation. (2008)
  • Author(s): Umebayashi K, Stenmark H, Yoshimori T.
  • Journal Title: Mol Biol Cell. 19 Pages: 3454-3462
  • Peer Reviewed
• [Journal Article] Autophagic control of listeria through intracellular innate immune recognition in drosophila. (2008)
  • Author(s): Yano T, Mita s, Ohmori H, Oshima Y, Fujimoto Y, Ueda R, Takada H, Goldman WE, Fukase K, Silverman N, Yoshimori I, Kurata S.
  • Journal Title: Nat Immunol. 9 Pages: 908-916
  • Peer Reviewed
• [Journal Article] An Atg4B Mutant Hampers the Lipidation of LC3 Paralogues and Causes Defects in Autophagosome Closure. (2008)
  • Author(s): Fujita N, Hayashi M, Fukumoto H, Omori H, Yamamoto A, Noda T, Yoshimori T.
  • Journal Title: Mol Biol Cell. 19 Pages: 4651-4659
  • Peer Reviewed
• [Journal Article] DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death. (2008)
  • Author(s): Gozuacik D, Bialik s, Raveh T, Mitou G, Shohat G, Sabanay H, Mizushima N, Yoshimori T, Kimchi A.
  • Journal Title: Cell Death Differ. 15 Pages: 1875-1886
  • Peer Reviewed
• [Journal Article] Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1 beta 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, Akira s. (^*These authors contributed equally to this work. )
  • Journal Title: Nature. 456 Pages: 264-268
  • Peer Reviewed
• [Journal Article] Nucleotide-Dependent Conformational Changes and Assembly of the AAA ATPase SKD1/VPS4B (2008)
  • Author(s): Inoue M, Kamikubo H, Kataoka M, Kato R, Yoshimori T, Wakatsuki S, Kawasaki M
  • Journal Title: Traffic. 9 Pages: 2180-2189
  • Peer Reviewed
• [Presentation] 分解系ロジスティクスの疾患における役割と作動機構 (2009)
  • Author(s): 吉森 保
  • Organizer: 特定領域研究「トラフィック」終了・新学術領域研究「ロジスティクス」発足合同シンポジウム
  • Place of Presentation: 航空会館(東京)
  • Year and Date: 2009-01-29
• [Presentation] Tuning Autophagy and Heterophagy (2009)
  • Author(s): 吉森保
  • Organizer: 第61回日本細胞生物学会大会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] Mechanistic Insight into Membrane Dynamics in Mammalian Autophagy (2009)
  • Author(s): Tamotsu Yoshimori
  • Organizer: Gordon Research Conference "Molecular Membrane Biology"
  • Place of Presentation: Proctor Academy, Andover, NH, USA
• [Presentation] Autophagy : Molecular Machinery and Roles in Diseases (2009)
  • Author(s): Tamotsu Yoshimori
  • Organizer: The 7th CBD (ARC Centre of Excellence in Biote chnology & Development) Scientific Meeting
  • Place of Presentation: The Country Place Retre at, Kalorama, Victoria, A ustralia
• [Presentation] Beclin1 Complexes, Salmonella, and Atg16L (2009)
  • Author(s): 吉森保
  • Organizer: 5th International Symposium on Autophagy
  • Place of Presentation: 大津プリンスホテル
• [Presentation] Binding Rubicon to Cross the Rubicon (2009)
  • Author(s): Tamotsu Yoshimori
  • Organizer: EMBO Conference on : Autophagy, Cell Biology, Physiology and Pathology
  • Place of Presentation: Monte Verita, Ascona, Switzerland
• [Presentation] Membrane Biogenesis and Regulatory Mechanisms in Autophagy (2009)
  • Author(s): 吉森保
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 細胞内自己消化システム・オートファジーによる生体防御 (2008)
  • Author(s): 吉森 保
  • Organizer: 日本細菌学会関東支部総会特別講演
  • Place of Presentation: 生命の森リゾート(千葉)
  • Year and Date: 2008-10-24
• [Presentation] Autophagy : Molecular Machinery and Role in Cellular Defense (2008)
  • Author(s): Tamotsu Yoshimori
  • Organizer: Korean Society of Medical Biochemistry and Molecular Biology Annual International Conference : In Commemoration of the 60th KSMBMB Anniversary, Symposium SY17 : Autophagy and Human Diseases
  • Place of Presentation: Seoul, Korea
• [Presentation] Mechanistic Insight into Membrane Dynamics in Mammalian Autophagy (2008)
  • Author(s): Tamotsu Yoshimori
  • Organizer: Center for the Study of Inflammatory Bowel Disease 18th Annual Workshop on Autophagy in Immunity
  • Place of Presentation: Boston, USA
• [Presentation] Molecular Machinery of Autophagy and Its Role in Diseases (2008)
  • Author(s): Tamotsu Yoshimori
  • Organizer: 11th Western Pacific Cingress on Chemotherapy and Infectious Diseases, Symposium 9 : Invasive Group A Streptococcal Infections
  • Place of Presentation: Taipei, Taiwan
• [Presentation] Autophagy as a Cellular Defense System against Pathogens and Unfolding Proteins (2008)
  • Author(s): Tamotsu Yoshimori
  • Organizer: BMB2008 (第3 1回日本分子生物学会年会・第8 1回日本生化学会大会合同大会)Symposium 3S3 : lntracellular Logistics : Approach to Pathophysiology of Membrane Traffic
  • Place of Presentation: 神戸ポーピアホテル
• [Book] Methods Enzymol. 452 (2009)
  • Author(s): Kimura s, Fujita N, Noda T, Yoshimori T.
  • Publisher: Academic Press
• [Book] 分子細胞生物学辞典(第2版) (2008)
  • Author(s): 吉森 保
  • Publisher: (株)東京化学同人
• [Remarks]
  • URL: http://www.biken.osaka-u.ac.jp/act/act_yoshimori.php
• [Remarks]
  • URL: http://www.biken.osaka-u.ac.jp/act/act_yoshimori.php