• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Roles of Pre-emptive pathway in the protein quality control.

Research Project

Project/Area Number 17H03657
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionTokyo Metropolitan University

Principal Investigator

Kawahara Hiroyuki  首都大学東京, 理学研究科, 教授 (70291151)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2017: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywordspreemptive pathway / BAG6 / Ubiquitin / Proteasome / Membrane protein / Protein degradation / プロテアソーム / タンパク質の品質管理 / 膜タンパク質 / ユビキチン / BAG6複合体 / UBQLN4 / 1型糖尿病 / 神経変成疾患 / タンパク質品質管理 / プレエンプティヴ品質管理 / 神経変性疾患 / 細胞内不良タンパク質 / E3リガーゼ
Outline of Final Research Achievements

GDP-bound cytoplasmic forms of Rab proteins are prone to aggregation due to the exposure of hydrophobic groups but the machinery that determines the fate of Rab species in the cytosol has not been elucidated in detail. In this study, we find that BAG6 predominantly recognizes a cryptic portion of GDP-associated Rab8a, while its major GTP-bound active form is not recognized. The hydrophobic residues of the Switch I region of Rab8a are essential for its interaction with BAG6 and the degradation of GDP-Rab8a via the ubiquitin-proteasome system . BAG6 prevents the excess accumulation of inactive Rab8a, whose accumulation impairs intracellular membrane trafficking. From these observations, we suggest that Rab proteins represent a novel set of substrates for BAG6, and the BAG6-mediated pathway is associated with the regulation of membrane vesicle trafficking events in mammalian cells.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、研究代表者が世界に先駆けて見出した独創的、かつ先駆的な研究成果を発展的にふまえた研究展開の一環である。本研究により、プレエンプティヴ品質管理の破綻が引き起こす疾患発症の全く新しい原理解明に貢献できた。
本研究は、ユビキチン系の制御機構と相携える重要な研究であり、新合成タンパク質の動態制御の基礎研究から、不良膜タンパク質の異常凝集に起因する各種病態発症の分子機構解明へと新領域を開拓することが充分に見込まれる。本研究で得られた情報・基盤技術はどの多細胞生物にも応用可能で、知的資産の形成に資することと同時に、人類社会に与える革新的インパクトも極めて大きい。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (30 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (4 results) Journal Article (9 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 9 results,  Open Access: 6 results) Presentation (12 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Book (2 results) Remarks (3 results)

  • [Int'l Joint Research] University of Cambridge/MRC(英国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] University of Cambridge(英国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] University of California, San Francisco(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] University of manchester(英国)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] BAG6 contributes glucose uptake by supporting the cell surface translocation of the glucose transporter GLUT4.2020

    • Author(s)
      Mimami, S., Yokota, N., and Kawahara, H.
    • Journal Title

      Biol. Open.

      Volume: 9 Pages: 477-489

    • DOI

      10.1242/bio.047324

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cytoplasmic control of Rab family small GTPases through BAG62019

    • Author(s)
      Takahashi Toshiki、Minami Setsuya、Tsuchiya Yugo、Tajima Kazu、Sakai Natsumi、Suga Kei、Hisanaga Shin‐ichi、Ohbayashi Norihiko、Fukuda Mitsunori、Kawahara Hiroyuki
    • Journal Title

      EMBO reports

      Volume: 20 Issue: 4

    • DOI

      10.15252/embr.201846794

    • NAID

      120007127921

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A molecular triage process mediated by RING finger protein 126 and BCL2-associated athanogene 6 regulates degradation of G0/G1 switch gene 22019

    • Author(s)
      Kamikubo Kenta、Kato Hisakazu、Kioka Hidetaka、Yamazaki Satoru、Tsukamoto Osamu、Nishida Yuya、Asano Yoshihiro、Imamura Hiromi、Kawahara Hiroyuki、Shintani Yasunori、Takashima Seiji
    • Journal Title

      Journal of Biological Chemistry

      Volume: 294 Issue: 40 Pages: 14562-14573

    • DOI

      10.1074/jbc.ra119.008544

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TAS-203, an oral phosphodiesterase 4 inhibitor, suppresses goblet cell hyperplasia and MUC5AC production in rodent models.2019

    • Author(s)
      Demizu, S., Asaka, M., Kawahara, H. and Sasaki, E.
    • Journal Title

      Eur. J. Pharmacol.

      Volume: 849 Pages: 22-29

    • DOI

      10.1016/j.ejphar.2019.01.068

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] BAG6 deficiency induces mis-distribution of mitochondrial clusters under depolarization.2019

    • Author(s)
      Hayashishita, M., Kawahara, H., and Yokota N.
    • Journal Title

      FEBS Open Bio.

      Volume: 9 Issue: 7 Pages: 1281-1291

    • DOI

      10.1002/2211-5463.12677

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel phosphorelay-dependent control of ZFP36L1 protein during the cell cycle.2018

    • Author(s)
      Kondo, M., Noguchi, A., Matsuura, Y., Shimada, M., Yokota, N., Kawahara, H.
    • Journal Title

      Biochem. Biophys. Res. Comm.

      Volume: in press Issue: 2 Pages: 387-393

    • DOI

      10.1016/j.bbrc.2018.04.212

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ZFP36L2 is a cell cycle-regulated CCCH protein necessary for DNA lesion-induced S-phase arrest2018

    • Author(s)
      Noguchi Aya、Adachi Shungo、Yokota Naoto、Hatta Tomohisa、Natsume Tohru、Kawahara Hiroyuki
    • Journal Title

      Biology Open

      Volume: 7

    • DOI

      10.1242/bio.031575

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Deubiquitylases USP5 and USP13 are recruited to and regulate heat-induced stress granules through their deubiquitylating activities2018

    • Author(s)
      Xie Xuan、Matsumoto Shunsuke、Endo Akinori、Fukushima Toshiaki、Kawahara Hiroyuki、Saeki Yasushi、Komada Masayuki
    • Journal Title

      Journal of Cell Science

      Volume: 131 Issue: 8 Pages: 210856-210856

    • DOI

      10.1242/jcs.210856

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Elimination of a signal-sequence uncleaved form of defective HLA protein through BAG6.2017

    • Author(s)
      Yamamoto, K., Hayashishita, M., Minami, S., Suzuki, K., Hagiwara, T., Noguchi, A., and Kawahara, H.
    • Journal Title

      Sci. Rep.

      Volume: 7 Issue: 1 Pages: 1-10

    • DOI

      10.1038/s41598-017-14975-9

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Regulatory mechanism for localization of RNA binding protein ZFP36L12019

    • Author(s)
      Matsuura, Y., Noguchi, A., Yokota, N., Kawahara, H.
    • Organizer
      Cold Spring Harbor meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 不良ポリペプチドを強固に認識する新規プローブDOBLEの開発2019

    • Author(s)
      宮田宗太郎、川原裕之
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] プレエンプティヴ経路特異的Ubデコーダーの生理的意義解明2019

    • Author(s)
      川原裕之
    • Organizer
      第2回ユビキチン研究会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] BAG6 regulates cytoplasmic pool of Rab family small GTPases.2018

    • Author(s)
      Kawahara, H., Minami, S., Takahashi, T.
    • Organizer
      日本分子生物学会41回年会ワークショップ
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] BAG6が標的とする新規Rabファミリータンパク質の同定とその意義2018

    • Author(s)
      田島佳寿、高橋俊樹、大林典彦、福田光則、川原裕之
    • Organizer
      日本分子生物学会第41回年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Rab特異的シャペロンタンパク質GDIとBAG6の相互作用解析2018

    • Author(s)
      泉田采音、林下瑞希、高橋俊樹、川原裕之
    • Organizer
      日本分子生物学会第41回年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] BAG6複合体を介した不良インスリン認識機構の解明2018

    • Author(s)
      淺沼真冬、南雪也、鈴木理滋、川原裕之
    • Organizer
      日本分子生物学会第41回年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 酸化ストレス存在下のBAG6複合体の役割2017

    • Author(s)
      横田直人、川原裕之
    • Organizer
      第40回日本分子生物学会 第90回日本生化学会 生命科学系合同年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] BAG6依存的なRab-GTPase分解機構の解明2017

    • Author(s)
      高橋俊樹、川原 裕之
    • Organizer
      第40回日本分子生物学会 第90回日本生化学会 生命科学系合同年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ミトコンドリアタンパク質を標的とするBAG6新規機能の探索2017

    • Author(s)
      6.林下瑞希、川原 裕之
    • Organizer
      第40回日本分子生物学会 第90回日本生化学会 生命科学系合同年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ミスローカライズしたGPIアンカー型タンパク質の代謝におけるBAG6の機能解析2017

    • Author(s)
      大野靖枝、横田直人、川原 裕之
    • Organizer
      第40回日本分子生物学会 第90回日本生化学会 生命科学系合同年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] UBQLN4の基質認識機構の解明2017

    • Author(s)
      鈴木勘司、鈴木理滋、川原裕之
    • Organizer
      第40回日本分子生物学会 第90回日本生化学会 生命科学系合同年会
    • Related Report
      2017 Annual Research Report
  • [Book] 生化学2020

    • Author(s)
      1.川原 裕之、南 雪也、宮内 真帆、高橋 俊樹
    • Total Pages
      6
    • Publisher
      日本生化学会
    • Related Report
      2019 Annual Research Report
  • [Book] 医学のあゆみ2018

    • Author(s)
      川原裕之
    • Total Pages
      8
    • Publisher
      医歯薬出版株式会社
    • Related Report
      2018 Annual Research Report
  • [Remarks] 東京都立大学理学部生命科学科ホームページ

    • URL

      https://www.biol.se.tmu.ac.jp/labo.asp?ID=celche

    • Related Report
      2019 Annual Research Report
  • [Remarks] 首都大学東京 生命科学ホームページ

    • URL

      http://www.biol.se.tmu.ac.jp/labo.asp?ID=celche

    • Related Report
      2018 Annual Research Report
  • [Remarks] 首都大学東京 生命科学専攻ホームページ

    • URL

      http://www.biol.se.tmu.ac.jp/labo.asp?ID=celche

    • Related Report
      2017 Annual Research Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi