リソソームを中心とした輸送ネットワークの分子機構と機能

• Project/Area Number: 15079209
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka University (2006-2007); National Institute of Genetics (2003-2005)
• Principal Investigator: 吉森 保 Osaka University, 微生物病研究所, 教授 (60191649)
• Project Period (FY): 2003 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥65,900,000 (Direct Cost: ¥65,900,000); Fiscal Year 2007: ¥11,300,000 (Direct Cost: ¥11,300,000); Fiscal Year 2006: ¥11,700,000 (Direct Cost: ¥11,700,000); Fiscal Year 2005: ¥11,700,000 (Direct Cost: ¥11,700,000); Fiscal Year 2004: ¥15,600,000 (Direct Cost: ¥15,600,000); Fiscal Year 2003: ¥15,600,000 (Direct Cost: ¥15,600,000)
• Keywords: リソソーム / タンパク質分解 / エンドソーム / オートファジー / EGF 受容体 / ユビキチン / 歯周病菌 / リン脂質 / たんぱく質分解 / Atgたんぱく質 / フォスファチジルエタノールアミン / メンブレントラフィック / Tom1 / 分解 / たんぱく質の凝集 / ポリグルタミン / 微小管 / 病原性細菌 / 自然免疫 / ラフト / AAA型ATPase / SKD1 / コレステロール

Research Abstract

分解オルガネラであるリソソームは、細胞内外の物質を消化する主要な場である。分解の対象となる物をリソソームに運び込むために、メンブレントラフィックによる輸送ネットワークが細胞内に張り巡らされている。ネットワークは細胞外から取り込まれた分子が辿るエンドソーム系経路と、細胞自身め構成成分が運ばれるオートファジー経路からなる。本研究は、リソソームを巡る輸送ネットワークの膜ダイナミクスの分子メカニズムと細胞や組織・個体における機能的意義の解明を目指すものである。本年度の成果は以下の通りである。1)EGF受容体は細胞膜からエンドソームに運ばれるまで常にユビキチン化酵素(E2及びE3)と共におり、それらによるポリユビキチン化がリソソームへの選別に必須であることを示した。EGF受容体をユビキチン化するE2の特定に成功し、従来言われていたものとは異なるものであることも明らかにした。2)歯周病菌P.grngivalisが宿主細胞に侵入する際、まずα5β1インテグリンに結合後脂質ラフトにRac1をリクルートしそれによりアクチン重合を促進し細胞内に入り込むことが、菌成分を付着したビーズを用いたアッセイ系により判明した。3)新たに同定した2種の新規Beclin結合タンパク質が、それぞれオートファジーをオートファゴソーム形成の段階で正と負に調節することを見出した。4)オートファジーに必須のリン脂質PI3Pについて、その合成酵素のみならず分解酵素(フォスファターゼ)もオートファジーの制御に重要であることを示した。

Research Products

• [Journal Article] A single amino acid mutation in hepatitis C virus NS5A disrupting FKBP8 interaction impairs viral replication. (2008)
  • Author(s): Okamoto, T・Omori, H・Haname, Y・Abe, T・Nishimura, Y・Suzuki, T・Miyamura, T・Yoshimori, T・Moriishi, K・Matsuura, Y.
  • Journal Title: J Virol. Jan.23
  • Peer Reviewed
• [Journal Article] Human TRME-8 Is Involved in Membrane Trafficking through Early Endosomes. (2008)
  • Author(s): Fujibayashi, A・Taguchi, T・Misaki, R・Ohtani, M・Dohmae, N・Takio, K・Yamada, M・Gu, J・Yamakami, M・Fukuda, M・Waguri, S・Uchiyama, Y・Yoshimori, T・Sekiguchi, K.
  • Journal Title: Cell Struct. Funct. Feb.6
  • Peer Reviewed
• [Journal Article] GFP-like Proteins Stably Accumulate in Lysosomes. (2008)
  • Author(s): Katayama, H・Yamamoto, A・Mizushima, N・Yoshimori, T・Miyawaki, A.
  • Journal Title: Cell Struct Funct. Feb.6 Epub
  • NAID: 130004053862
  • Peer Reviewed
• [Journal Article] The Atg16L Complex Specities 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. (In press)
  • Peer Reviewed
• [Journal Article] The anticancer drug imatinib induces cellular autophagy. (2007)
  • Author(s): Ertmer, A・Huber, V・Gilchi, S・Yoshimori, T・Erfle, V・Duyster, J・Elsasser, HP・Schatzl, HM.
  • Journal Title: Leukemia. 21 Pages: 936-942
  • Peer Reviewed
• [Journal Article] Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. (2007)
  • Author(s): Ding, WX・Ni, HM・Gao, W・Yoshimori, T・Stolz, DB・Ron, D・Yin, XM.
  • Journal Title: Am J Pathol. 171 Pages: 513-524
  • Peer Reviewed
• [Journal Article] Role of Hrs in maturation of autophagosomes in mammalian cells. (2007)
  • Author(s): Tamai, K・Tanaka, N・Nara, A・Yamamoto, A・Nakagawa, I・Yoshimori, T・Ueno, Y・Shimosegawa, T・Sugamura, K.
  • Journal Title: Biochem Biophys Res Commun. 360 Pages: 721-727
  • Peer Reviewed
• [Journal Article] Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. (2007)
  • Author(s): Kimura, S・Noda, T・Yoshimori, T.
  • Journal Title: Autophagy. 3 Pages: 452-460
  • Peer Reviewed
• [Journal Article] The C/EBPbeta isoform 34-kDa LAP is responsible for NF-IL-6-mediated gene indction in activated macrophages, but is not essential for intracellular bacteria bacteria killing. (2007)
  • Author(s): Uematsu, S・Kaisho, T・Tanaka, T・Matsumoto, M・Yamakami, M・Omori, H・Yamamoto, M・Yoshimori, T・Akira, S.
  • Journal Title: J Immunol. 179 Pages: 5378-5386
  • Peer Reviewed
• [Journal Article] Maturation of fimbria precursor protein by exogenous gingipains in Porphyromonas gingivalis gingipain-null mutant. (2007)
  • Author(s): Kato, T・Tsuda, T・Omori, H・Kato, T・Yoshimori, T・Amano, A.
  • Journal Title: FEMS Microbiol Lett. 273 Pages: 96-102
  • Peer Reviewed
• [Journal Article] Virulence of Porphyromonas gingivalis is altered by substitution of fimbria gene with different genotype. (2007)
  • Author(s): Kato T, Kawai S, Nakano K, Inaba H, Kuboniwa M, Nakagawa I, Tsuda K, Omori H, Ooshima T, Yoshimori T, Amano A
  • Journal Title: Cell Microbiol. 9 Pages: 753-765
• [Journal Article] Nordihydroguaiaretic acid affects multiple dynein-dynactin functions in interphase and mitotic cells. (2007)
  • Author(s): Arasaki K, Tani K, Yoshimori T, Stephens DJ, Tagaya M
  • Journal Title: Mol Pharmacol. 71 Pages: 454-460
• [Journal Article] Protective role of autophagy against Vibrio cholerae cytolysin, a pore-forming toxin from V. cholerae (2007)
  • Author(s): Gutierrez MG, Saka HA, Chinen I, Zoppino FCM, Yoshimori T, Bocco JL, Colombo MI
  • Journal Title: Proc. Natl. Acad. Sci. 104 Pages: 1829-1834
• [Journal Article] The anticancer drug imatinib induces cellular autophagy. (2007)
  • Author(s): Ertmer A, Huber V, Gilch S, Yoshimori T, Erfle V, Duyster J, Elsasser HP, Schatzl HM
  • Journal Title: Leukemia Mar.1(Epub)
• [Journal Article] Intracellular inclusions containing mutant □1-antitrypsin Z are propagated in the absence of autophagic activity (2006)
  • Author(s): Kamimoto T, Shouji S, Hidvegi T, Mizushima N, Umebayashi K, Perlmutter D H, Yoshimori T
  • Journal Title: J. Biol. Chem. 281 Pages: 4467-4476
• [Journal Article] Autophagy Controls Salmonella Infection in Response to Damage to the Salmonella-containing Vacuole. (2006)
  • Author(s): Birmingham C L, Smith A C, Bakowski M A, Yoshimori T, Brumell J H
  • Journal Title: J. Biol. Chem. 281 Pages: 11374-11383
• [Journal Article] Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. (2006)
  • Author(s): Shibata M, Lu T, Furuya T, Degterev A, Mizushima N, Yoshimori T, Macdonald M, Yankner B, Yuan J
  • Journal Title: J. Biol. Chem. 281 Pages: 14474-14485
• [Journal Article] CHMP5 is essential for late endosome function and down-regulation of receptor signaling during mouse embryogenesis. (2006)
  • Author(s): Shim J H, Xiao C, Hayden M S, Lee K Y, Trombetta E S, Pypaert M, Nara A, Yoshimori T, Wilm B, Erdjument-Bromage H, Tempst P, Hogan B L, Mellman I, Ghosh S
  • Journal Title: J. Cell Biol. 172 Pages: 1045-1056
• [Journal Article] Survival of parvovirus B19-infected cells by cellular autophagy. (2006)
  • Author(s): Nakashima A, Tanaka N, Tamai K, Kyuuma M, Ishikawa Y, Sato H, Yoshimori T, Saito S, Sugamura K
  • Journal Title: Virology. 349 Pages: 254-263
• [Journal Article] Cholesterol depletion facilitates ubiquitylation of NPC1 and its association with SKD1/Vps4. (2006)
  • Author(s): Ohsaki Y, Sugimoto Y, Suzuki M, Hosokawa H, Yoshimori T, Davies JP, Ioannou YA, Vanier MT, Ohno K, Ninomiya H
  • Journal Title: J Cell Sci. 119 Pages: 2643-2653
• [Journal Article] Rotavirus NSP4 induces a novel vesicular compartment regulated by calcium and associated with viroplasms. (2006)
  • Author(s): Berkova Z, Crawford SE, Trugnan G, Yoshimori T, Morris AP, Estes MK
  • Journal Title: J Virol. 80 Pages: 6061-6071
• [Journal Article] ALIS are Stress-Induced Protein Storage Compartments for Substrates of the Proteasome and Autophagy (2006)
  • Author(s): Szeto J, Kaniuk NA, Canadien V, Nisman R, Mizushima N, Yoshimori T, Bazett-Jones DP, Brumell JH
  • Journal Title: Autophagy 2 Pages: 189-199
• [Journal Article] Intracellular inclusions containing mutant α1-antitrypsin Z are propagated in the absence of autophagic activity (2006)
  • Author(s): Kamimoto T, Shisako S, Hidvegi T, Mizushima N, Umebayashi K, Perlmutter D H, Yoshimori T.
  • Journal Title: J.Biol.Chem. 281 Pages: 4467-4476
• [Journal Article] Endothelial nitric oxide synthase antisense (NOS3AS) gene encodes an autophagy-related protein (APG9-like2) highly expressed in trophoblast (2005)
  • Author(s): Yamada T, Carson A R, Caniggia I, Umebayashi K, Yoshimori T, Nakabayashi K, Scherer S W
  • Journal Title: J.Biol.Chem. 280 Pages: 18283-18290
• [Journal Article] Small GTPase proteins Rin and Rit bind to Par6 GTP-dependently, and regulate cell transformation (2005)
  • Author(s): Hoshino M, Yoshimori T, Nakamura S
  • Journal Title: J.Biol.Chem. 280 Pages: 22868-22874
• [Journal Article] Sera from patients with type 2 Diabetes and Neuropathy Induce Autophagy and Colocalization with Mitochondria in SY5Y cells (2005)
  • Author(s): Towns R, Kabeya Y, Yoshimori T, Guo C, Shangguan Y, Hong S, Kaplan M, Klionsky D J, Wiley J W
  • Journal Title: Autophagy 1 Pages: 163-170
• [Journal Article] Regulation of epidermal growth factor receptor down-regulation by UBPY mediated deubiquitination at endosomes (2005)
  • Author(s): Mizuno E, Iura T, Mukai A, Yoshimori T, Kitamura N, Komada M.
  • Journal Title: Mol Biol Cell. 16 Pages: 5163-5174
• [Journal Article] Induced expressions of Rab24 GTPase and LC3 in nerve-injured motor neurons (2005)
  • Author(s): Egami Y, Kiryu-Seo S, Yoshimori T, Kiyama H.
  • Journal Title: Biochem Biophys Res Commun. 337 Pages: 1206-1213
• [Journal Article] Molecular dissection of internalization of Porphyromonas gingivalis by cells using fluorescent beads coated with bacterial membrane vesicle (2005)
  • Author(s): Tsuda K, Amano A, Umebayashi K, Inaba H, Nakagawa I, Nakanishi Y, Yoshimori T.
  • Journal Title: Cell Struct.Funct. 30 Pages: 81-91
  • NAID: 130004137501
• [Journal Article] Escape of Intracellular Shigella from Autophagy (2005)
  • Author(s): Ogawa M, Yoshimori T, Suzuki T, Sagara H, Mizushima N, Sasakawa
  • Journal Title: Science 307 Pages: 727-731
• [Journal Article] Inhibition of Macroautophagy Triggers Apoptosis (2005)
  • Author(s): Boya P, Gonzalez-Polo R-A, Casares N, Perfettini J-L, Dessen P, Larochette N, Metivier D, Meley D, Souquere S, Yoshimori T, Pierron G, Codogno P, Kroemer G
  • Journal Title: Mol.Cell.Biol. 25 Pages: 1025-1040
• [Journal Article] Endothelial nitric oxide synthase antisense (NOS3AS) gene encodes an autophagy-related protein (APG9-like2) highly expressed in trophoblast (2005)
  • Author(s): Yamada T, Carson A R, Caniggia I, Umebayashi K, Yoshimori T, Nakabayashi K, Scherer S W
  • Journal Title: J.Biol.Chem. (On line)
• [Journal Article] In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker (2004)
  • Author(s): Mizushima N, Yamamoto A, Matsu M, Yoshimori T, Ohsumi Y
  • Journal Title: Mol.Biol.Cell 15 Pages: 1101-1111
• [Journal Article] Coronavirus Replication Complex Formation Utilizes Components of Cellular Autophagy (2004)
  • Author(s): Prentice E W., Jerome G, Yoshimori T, Mizushima N, Denison M R.
  • Journal Title: J.Biol.Chem. 279 Pages: 10136-10141
• [Journal Article] LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. (2004)
  • Author(s): Kabeya Y, Mizushima N, Hitani-Okamoto S, Ohsumi Y, Yoshimori T.
  • Journal Title: J.Cell Sci 117 Pages: 2805-2812
• [Journal Article] Mammalian class E Vps proteins, SBP1 and mVps2/CHMP2A, interact with and regulate the function of an AAA-ATPase SKD1/Vps4B (2004)
  • Author(s): Fujita H, Umezuki Y, Imamura K, Ishikawa D, Uchimura S, Nara A, Yoshimori T, Hayashizaki Y, Kawai J, Ishidoh K, Tanaka Y., Himeno M.
  • Journal Title: J.Cell Sci. 117 Pages: 2997-3009
• [Journal Article] Alfy, a novel FYVE domain-containing protein associated with protein granules and autophagic membranes (2004)
  • Author(s): Birkeland H C G, Simonsen A, Gillooly D J, Mizushima N, Kuma A, Yoshimori T, Slagsvold T, Brech A, Stenmark H
  • Journal Title: J.Cell.Sci. 117 Pages: 4239-4251
• [Journal Article] Role of autophagy during the early neonatal starvation period (2004)
  • Author(s): Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N
  • Journal Title: Nature 432 Pages: 1032-1036
• [Journal Article] Autophagy defenses cells against invading group A Streptococcus (2004)
  • Author(s): Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, Kamimoto T, Nara A, Funao J, Nakata M, Tsuda K, Hamada S, Yoshimori T
  • Journal Title: Science 306 Pages: 1037-1040
• [Presentation] Where they come from?: Mechanistic insight into autophagosome formation in mammals (2008)
  • Author(s): Tamotsu, Yoshimori
  • Organizer: Gordon Research Conference Autophagy In Stress, Development And Disease
  • Place of Presentation: Ventura, CA, USA
• [Presentation] Autophagy as A Cellular Defense System (2007)
  • Author(s): Tamotsu, Yoshimori
  • Organizer: 2007 International RIMD-CVRDC Joint Symposium
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2007-12-18
• [Presentation] たんぱく質と膜が造る細胞内物流システム (2007)
  • Author(s): 吉森 保
  • Organizer: 科学技術振興機構戦略的創造研究推進事業(CREST)研究領域「たんぱく質の構造・機能と発現メカニズム」平成14年度採択課題終了シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2007-11-15
• [Presentation] オートファジー:分子機構と疾患における役割 (2007)
  • Author(s): 吉森 保
  • Organizer: 大阪大学21世紀COE「疾患関連糖鎖・タンパク質の統合的機能解析」若手セミナー
  • Place of Presentation: 大阪大学医学部
  • Year and Date: 2007-10-24
• [Presentation] オートファジー:生体防御にも働く細胞内自己消化システム (2007)
  • Author(s): 吉森 保
  • Organizer: 家畜DNA西郷シンポジウム
  • Place of Presentation: 福島県西白河郡
  • Year and Date: 2007-10-02
• [Presentation] 生体防御機構としてのオートファジー:細菌感染とフォールディング病 (2007)
  • Author(s): 吉森 保
  • Organizer: 文科省科研費特定領域研究「タンパク質分解による細胞・個体機能の制御」公開シンポジウム「オートファジー:病態に迫る!」
  • Place of Presentation: 東京
  • Year and Date: 2007-09-22
• [Presentation] Autophagy:new insights into its molecular machinery and functions (2007)
  • Author(s): Tamotsu, Yoshimori
  • Organizer: The invited seminar in Institute of Molecular and Cell Biology
  • Place of Presentation: Singapore
  • Year and Date: 2007-09-12
• [Presentation] 生体防御とオニトファジー (2007)
  • Author(s): 吉森 保
  • Organizer: 第18回日本生体防御学会学術総会特別講演
  • Place of Presentation: 福岡
  • Year and Date: 2007-07-26
• [Presentation] ベールを脱ぐオートファジー:生体防御にも働く細胞内自己消化システム (2007)
  • Author(s): 吉森 保
  • Organizer: 熊本大学大学院医学教育部セミナー
  • Place of Presentation: 熊本大学大学院医学教育部
  • Year and Date: 2007-07-04
• [Presentation] New insight into Molecular Mechanisms of the Canonical and Specialized Autophagy (2007)
  • Author(s): Tamotsu, Yoshimori
  • Organizer: Keystone Symposia on"Autophagy in Health and Disease"
  • Place of Presentation: Monterey, Califbmia, U.S.A.
• [Presentation] Autophagy as a cellular guardian against bacteria and aggregate-prone proteins (2007)
  • Author(s): Tamotsu, Yoshimori
  • Organizer: ELSO conference 2007, Subgroup meeting one-Autophagy
  • Place of Presentation: Dresden, Germany
• [Presentation] Autophagy:Molecular Machinery and Role in Cellular Defense (2007)
  • Author(s): Tamotsu, Yoshimori
  • Organizer: The 20th Naito Conference on "Innate Immunity in Medicine and Biology III"
  • Place of Presentation: Kanagawa, Japan
• [Presentation] Membrane Dynamics and Cellular Defense Function of Autophagy (2007)
  • Author(s): Tamotsu, Yoshimori
  • Organizer: Internatinal Symposium on Membrane Traffic
  • Place of Presentation: Awajishima, Japan
• [Book] 生化学辞典(第4版)リソソームへの輸送 (2007)
  • Author(s): 吉森 保
  • Total Pages: 1616
  • Publisher: (株)東京化学同人
• [Book] 生化学辞典(第4版) (リソソームへの輸送) (2007)
  • Author(s): 吉森 保
  • Publisher: 東京化学同人(印刷中)
• [Book] Autophagy eliminates Group A Streptococcus invading host cells (A Novel Immune Effector, Ed. Deretic V.) (Autophagy in Immunity and Infection) (2006)
  • Author(s): Amano A, Yoshimori T
  • Total Pages: 250
  • Publisher: WILEY-VCH
• [Remarks]
  • URL: http://www.biken.osaka-u.ac.jp/act/act_yoshimori.php
• [Publications] Saeki K, Hong Z, Nakatsu M, Yoshimori T, 他: "Insulin-dependent signaling regulates azurophil granule-selective macroautophagy in human myeloblastic cells."J.Leukoc.Biol.. 74. 1108-1116 (2003)
• [Publications] Ohashi M, Mizushima N, Kabeya Y, Yoshimori T.: "Localization of Mammalian NAD(P)H Steroid Dehydrogenase-like Protein on Lipid Droplets."J.Biol.Chem.. 278. 36819-36829 (2003)
• [Publications] Katoh K, Shibata H, Suzuki H, Nara A, Ishidoh K, Kominami E, Yoshimori T 他: "The ALG-2-interacting protein Alix associates with CHMP4b, a human homologue of yeast Snf7 that is involved in multivesicular body sorting."J.Biol.Chem.. 278. 39104-39113 (2003)
• [Publications] Kanazawa C, Morita E, Yamada M, Ishii N, Miura S, Asao H, Yoshimori T 他: "Effects of deficiencies of STAMs and Hrs, mammalian class E Vps proteins, on receptor downregulation"Biochem.Biophys.Res.Commun.. 309. 848-856 (2003)
• [Publications] Yamakami M, Yoshimori T, Yokosawa H.: "Tom 1, a VHS domain-containing protein, interacts with Tollip, ubiquitin, and clathrin"J.Biol.Chem.. 278. 52865-52872 (2003)
• [Publications] Mizushima N, Yamamoto A, Matsui M, Yoshimori T, 他: "In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker"Mol.Biol.Cell. 15. 1101-1111 (2004)
• [Publications] Yoshimori T, 他(共著): "Autophagy"Eurekah.com. 204-210 (2003)