プロテアソームを基軸としたタンパク質分解系の包括的研究

2010 Fiscal Year Annual Research Report

• Project/Area Number: 21000012
• Research Institution: Tokyo Metropolitan Organization for Medical Research
• Principal Investigator: 田中 啓二 (財)東京都医学総合研究所, 東京都臨床医学総合研究所, 理事 (10108871)
• Co-Investigator(Kenkyū-buntansha): 村田 茂穂 東京大学, 大学院・薬学系研究科, 教授 (20344070)
• Keywords: 蛋白質 / バイオテクノロジー / プロテオーム / 脳神経疾患 / 免疫学

Research Abstract

26Sプロテアソームは不要になった細胞内のタンパク質を選択的に分解するための大規模な細胞内装置である。本酵素は触媒機能を司る20S CP(Core Particle : 別名20Sプロテアソーム)の両端に調節ユニットである19S RP(Regulatory Particle)が会合した分子量250万の巨大で複雑な多成分複合体である。CPはα-Ringとβ-Ring(各々7種のα/βサブユニットから構成)がαββαの順で会合した円筒型粒子であり、RPは6個のATPase(Rpt1-6)と約15個のnon-ATPase(Rpn1-15)サブユニットがLid(蓋部)とBase(基底部)を構成している。本年、以下の4項目で顕著な成果を挙げた。(1)プロテアソームの遺伝学的研究においては、プロテアソーム分子集合因子(PAC1 : α-Ring形成因子)の条件的KOマウスを作出、このシャペロン依存性の20Sプロテアソーム形成がマウスの個体発生、脳の増殖・分化、肝臓の恒常性維持に必須であることを明らかにした。(2)われわれが作出した胸腺プロテアソーム欠損マウスと単一のMHCクラスI分子を持った遺伝子改変マウスとの交配実験から胸腺プロテアソームが胸腺におけるCD8^+Tリンパ球の正の選択を介したレパトア形成に関与していることを証明した。(3)オートファジー選択的基質であるp62がKeap1(酸化ストレス応答ユビキチンリガーゼ)に直接会合して(抗酸化/解毒応答)マスター転写因子Nrf2を解離・(核移行)活性化する新しいオートファジー障害依存性のストレス応答機構を発見した。(4)家族性パーキンソン病の原因遺伝子であるPINK1とParkinが介在したミトコンドリアの新しい品質管理(選択的オートファジーによる損傷ミトコンドリアのクリアランス/浄化)機構の発見とパーキンソン病の発症機構の解明に成功した。

Research Products

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• [Journal Article] The catalytic activity of Ubp6 enhances maturation of the proteasomal regulatory particle. (2011)
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• [Journal Article] Parkin Mediates Apparent E2-independent Monoubiquitination In Vitro and Contains an Intrinsic Activity that Catalyzes Polyubiquitination. (2011)
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• [Journal Article] Polyubiquitin conjugation to NEMO by triparite motif protein 23 (TRIM23) is critical in antiviral defense. (2010)
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• [Journal Article] Activity-based profiling reveals reactivity of the murine thymoproteasome-specific subunit beta5t. (2010)
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• [Journal Article] Ubiquitin accumulation in autophagy-deficinet mice is dependent on the Nrf2-mediated stress response pathway : a potential role for protein aggregation in autophagic substrate selection. (2010)
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• [Journal Article] Does impairment of the ubiquitin-proteasome system or the autophagy-lysosome pathway predispose individuals to neurodegenerative disorders such as Parkinson's disease? (2010)
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• [Journal Article] Lectin-like ERAD players in ER and cytosol. (2010)
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• [Journal Article] Role of thymic cortex-specific self-peptides in positive selection of T cells. (2010)
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• [Journal Article] Regulatory mechanisms involved in the control of ubiquitin homeostasis. (2010)
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• [Presentation] Parkinson's disease : a quality control disease of depolaized mitochondoria. (2011)
  • Author(s): Keiji Tanaka
  • Organizer: The 1^<st> small Korea/Japan symposium
  • Place of Presentation: Seoul, Korea(招待講演)
  • Year and Date: 20110127-20110129
• [Presentation] ユビキチン・プロテアソームシステムによるタンパク質分解 (2011)
  • Author(s): 田中啓二
  • Organizer: 京都産業大学・総合生命科学部 開設記念シンポジウム"タンパク質の一生と生命システム」
  • Place of Presentation: 京都(招待講演)
  • Year and Date: 2011-03-10
• [Presentation] 細胞内リサイクルシステム-新陳代謝の科学- (2011)
  • Author(s): 田中啓二
  • Organizer: 第5回炎症・脂質代謝・メタボリサーチフォーラム
  • Place of Presentation: 東京大学医学部教育研究棟、東京(招待講演)
  • Year and Date: 2011-02-12
• [Presentation] The PINK1/Parkin pathway controls mitochondrial homeostasis whose impairment causes Parkinson's disease. (2010)
  • Author(s): Keiji Tanaka
  • Organizer: Global COE International Symposium/Retreat 2010
  • Place of Presentation: Awaji Island, Japan(招待講演)
  • Year and Date: 20101105-20101106
• [Presentation] Autophagy and Parkinson's Disease (2010)
  • Author(s): Keiji Tanaka
  • Organizer: 1^<st> Sino-Japan Autophagy Symposium
  • Place of Presentation: Xi'an, China(招待講演)
  • Year and Date: 20101015-20101017
• [Presentation] In Depth Analysis of protein Degradation in the Life Science Field. (2010)
  • Author(s): 田中啓二
  • Organizer: 69^<th> Annual Meeting of The Japanese Cancer Association "Conquering Cancer and Collective Wisdom
  • Place of Presentation: 大阪(招待講演)
  • Year and Date: 20100922-20100924
• [Presentation] Assembly of Eukaryotic Proteasomes assisted by Molecular Chaperones" (2010)
  • Author(s): Keiji Tanaka
  • Organizer: The 3^<rd> International Symposium on Protein Community
  • Place of Presentation: Hotel Nikko Nara, Nara, Japan(招待講演)
  • Year and Date: 20100913-20100916
• [Presentation] Impairment of proteolytic homeostasis as cause of neurodegeneration (2010)
  • Author(s): Keiji Tanaka
  • Organizer: S1 JOINT SYMPOSIUM [Key Mechanisms in Neurodegeneration] PRION & ICN Congress
  • Place of Presentation: Salzburg, Austria(招待講演)
  • Year and Date: 20100908-20100912
• [Presentation] 私のプロテアソーム研究-免疫との予期しなかった遭遇- (2010)
  • Author(s): 田中啓二
  • Organizer: 千葉大学G-COEプログラム"免疫システム統御治療学"免疫学リトリート
  • Place of Presentation: 千葉生命の森リゾート、千葉(招待講演)
  • Year and Date: 20100904-20100905
• [Presentation] Autophagic Control of Mitochondrial Homeostasis and Neurodegeneration" [Mechanism underling the cause of Parkinson's Disease : The functions of Parkin/PINK1] (2010)
  • Author(s): Keiji Tanaka
  • Organizer: Proteolysis and Neurodegeneration : 5th INPROTEOLYSIS meeting, EMBO Workshop
  • Place of Presentation: Madrid, Spain(招待講演)
  • Year and Date: 20100504-20100507
• [Presentation] 細胞内リサイクルシステム-新陳代謝の科学- (2010)
  • Author(s): 田中啓二
  • Organizer: JSTさきがけ「代謝と機能制御」領域 研究報告会シンポジウム:特別講演
  • Place of Presentation: 東京大学弥生講堂・一條ホール、東京(招待講演)
  • Year and Date: 2010-12-13
• [Presentation] Role of Proteolysis in Liver Pathophysiology. (2010)
  • Author(s): Keiji Tanaka
  • Organizer: The 9^<th> JSH Single Topic Conference "NASH 2010"
  • Place of Presentation: Tokyo, Japan(招待講演)
  • Year and Date: 2010-11-19
• [Presentation] 私の履歴書 -プロテアソームを基軸としたタンパク質分解研究- (2010)
  • Author(s): 田中啓二
  • Organizer: 第15回病態プロテアーゼ学会学術集会"『日本学士院賞』受賞記念講演
  • Place of Presentation: 千里ライフサイエンスセンター、大阪(招待講演)
  • Year and Date: 2010-08-20
• [Presentation] 細胞内リサイクルシステム-新陳代謝と健康- (2010)
  • Author(s): 田中啓二
  • Organizer: 徳島大学市民公開講演会～生命の謎に迫る～
  • Place of Presentation: 長井記念ホール、徳島(招待講演)
  • Year and Date: 2010-07-31
• [Presentation] パーキンソン病の分子病態機序のブレイクススルー:Parkin/PINK1の機能"パーキンソン病の分子病態機序 (2010)
  • Author(s): 田中啓二、松田憲之、尾勝圭
  • Organizer: 新世代の神経学-Breakthrough to the NEXT STAGE-、第51回日本神経学会総会
  • Place of Presentation: 東京(招待講演)
  • Year and Date: 2010-05-22
• [Presentation] The Structure and Biological Functions of Proteasomes (+The Role of PINK1/Parkin in Mitophagy and Parkinson's Disease). (2010)
  • Author(s): 田中啓二
  • Organizer: 第62回日本細胞生物学会大会 (The 62nd Annual Meeting of the Japanese Society of Cell Biology)・特別講演
  • Place of Presentation: Osaka(招待講演)
  • Year and Date: 2010-05-20
• [Presentation] プロテアソーム:オーバービューと免疫研究の最前線 (2010)
  • Author(s): 田中啓二
  • Organizer: 第54回日本リウマチ学会総会・学術集会:特別講演
  • Place of Presentation: 神戸(招待講演)
  • Year and Date: 2010-04-23
• [Presentation] 蛋白質リサイクルシステムの意義とその破綻による疾病 (2010)
  • Author(s): 田中啓二
  • Organizer: 科学技術政策研究所シンポジウム:近未来への招待状～ナイスステップな研究者2009からのメッセージ～
  • Place of Presentation: 文部科学省第2講堂、東京(招待講演)
  • Year and Date: 2010-04-22
• [Book] Assembly and function of the proteasome. "Ubiquitin Family Modifiers and the Proteasome : Reviews and Protocols" (2011)
  • Author(s): Saeki, Y, Tanaka, K.
  • Publisher: Humana Press. SPRINGER SCIENCE+BUSINESS MEDIA, New York, (USA)(In press)
• [Remarks]
  • URL: http://www.igakuken.or.jp/