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p62によるオートファジーとストレス応答制御の統合的理解

Research Project

Project/Area Number 18F18099
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section外国
Research Field General medical chemistry
Research InstitutionJuntendo University (2019)
Niigata University (2018)

Principal Investigator

小松 雅明  順天堂大学, 医学(系)研究科(研究院), 教授 (90356254)

Co-Investigator(Kenkyū-buntansha) SANCHEZ-MARTIN PABLO  順天堂大学, 医学(系)研究科(研究院), 外国人特別研究員
Project Period (FY) 2018-04-25 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2019: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2018: ¥1,200,000 (Direct Cost: ¥1,200,000)
Keywordsオートファジー / p62 / NBR1 / Keap1 / Nrf2 / p62/SQSTM1 / 液-液相分離 / 筋萎縮性側索硬化症 / 前頭側頭型認知症 / 骨ページェット病
Outline of Annual Research Achievements

NBR1は、p62と同様のドメイン構造を有する選択的オートファジーアダプタータンパク質であり、ユビキチン化タンパク質、ペルオキシソーム、侵入細菌のオートファジー分解に関与することが報告されている。NBR1はN末端のPhox1 and Bem1p(PB1)ドメインを介してp62と結合し、オートファジーにより分解される選択的分解基質でもある。今回、我々は細胞内のp62液滴形成およびNrf2活性化におけるNBR1の役割を調べた。マウス初代培養肝細胞にNBR1を発現させるとオートファジーによるp62液滴の分解が特異的に阻害され、p62の蓄積・濃縮が起こるとともにNrf2の活性化に必要なS349のリン酸化が促進されることを見出した。マウス初代培養肝細胞において内因性NBR1はストレスに応じて発現量が上昇し、p62を介したNrf2の活性化が増進した。一方、NBR1を欠失したマウス初代培養肝細胞では、ストレスに応じたp62の蓄積・濃縮のみならず、Nrf2活性化も抑制されていた。これらのことは、NBR1はp62の液-液相分離を促進しp62液滴にKeap1を隔離することで、Nrf2を活性化させるストレス調節因子であることを意味する(EMBO Rep. 2020)。上述の研究成果に加えて、p62/SQSTM1あるいは選択的オートファジーの複数の総説を細胞生物学分野において影響力のある学術誌に上梓した(JMB 2019, JCB 2020)。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (20 results)

All 2020 2019 2018 Other

All Journal Article (8 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 8 results,  Open Access: 6 results) Presentation (9 results) (of which Int'l Joint Research: 7 results,  Invited: 7 results) Remarks (3 results)

  • [Journal Article] Heparan sulfate and clusterin: Cleaning squad for extracellular protein degradation2020

    • Author(s)
      Sanchez-Martin Pablo、Komatsu Masaaki
    • Journal Title

      Journal of Cell Biology

      Volume: 219 Issue: 3

    • DOI

      10.1083/jcb.202001159

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] NBR1‐mediated p62‐liquid droplets enhance the Keap1‐Nrf2 system2020

    • Author(s)
      Sanchez-Martin Pablo、Komatsu Masaaki
    • Journal Title

      EMBO reports

      Volume: 21 Issue: 3

    • DOI

      10.15252/embr.201948902

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Physiological Stress Response by Selective Autophagy2020

    • Author(s)
      Sanchez-Martin Pablo、Komatsu Masaaki
    • Journal Title

      Journal of Molecular Biology

      Volume: 432 Issue: 1 Pages: 53-62

    • DOI

      10.1016/j.jmb.2019.06.013

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Autophagy regulates lipid metabolism through selective turnover of NCoR12019

    • Author(s)
      Saito Tetsuya、Kuma Akiko、Sugiura Yuki、Ichimura Yoshinobu、Obata Miki、Kitamura Hiroshi、Okuda Shujiro、Lee Hyeon-Cheol、Ikeda Kazutaka、Kanegae Yumi、Saito Izumu、Auwerx Johan、Motohashi Hozumi、Suematsu Makoto、Soga Tomoyoshi、Yokomizo Takehiko、Waguri Satoshi、Mizushima Noboru、Komatsu Masaaki
    • Journal Title

      Nature Communications

      Volume: 10 Issue: 1 Pages: 41467-41467

    • DOI

      10.1038/s41467-019-08829-3

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Measuring Nonselective and Selective Autophagy in the Liver.2019

    • Author(s)
      Ueno T and Komatsu M
    • Journal Title

      Methods in Molecular Biology

      Volume: 1880 Pages: 535-540

    • DOI

      10.1007/978-1-4939-8873-0_34

    • ISBN
      9781493988723, 9781493988730
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] p62/SQSTM1 : ‘Jack of all trades’ in health and cancer.2019

    • Author(s)
      Sánchez-Martin P, Saito T, Komatsu M.
    • Journal Title

      FEBS J.

      Volume: 286 Issue: 1 Pages: 8-23

    • DOI

      10.1111/febs.14712

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] p62/SQSTM1-steering the cell through health and disease.2018

    • Author(s)
      Sánchez-Martin P, Komatsu M.
    • Journal Title

      J Cell Sci.

      Volume: 131 Issue: 21 Pages: 222836-222836

    • DOI

      10.1242/jcs.222836

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Attenuation of cGAS‐STING signaling is mediated by a p62/SQSTM1‐dependent autophagy pathway activated by TBK12018

    • Author(s)
      Prabakaran Thanes、...Paludan Soren R
    • Journal Title

      EMBO J.

      Volume: - Issue: 8

    • DOI

      10.15252/embj.201797858

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Selective turnover of p62-liquid droplets through autophagy2020

    • Author(s)
      Masaaki Komatsu
    • Organizer
      International Conference on Autophagy and Lysosomes
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Selective turnover of p62-liquid droplets through autophagy2019

    • Author(s)
      Masaaki Komatsu
    • Organizer
      Seoul National University Bioscience Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Selective turnover of p62-bodies through autophagy.2019

    • Author(s)
      Masaaki Komatsu
    • Organizer
      9th International Symposium on Autophagy
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Selective turnover of p62-liquid droplets through autophagy2019

    • Author(s)
      Masaaki Komatsu
    • Organizer
      Asian Pacific Prion Symposium 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Autophagy regulates lipid metabolism (Bioenergetics and NAFLD)2019

    • Author(s)
      Masaaki Komatsu
    • Organizer
      Asia Pacific Association for Study of Liver (APASL) meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Selective autophagy regulates lipid-oxidation through NCoR1-PPARα-axis2018

    • Author(s)
      Masaaki Komatsu
    • Organizer
      Keystone Symposia, Selective Autophagy
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Selective Autophagy Regulates Lipid-oxidation2018

    • Author(s)
      Masaaki Komatsu
    • Organizer
      24th IUBMB-15th FAOBMB Congress
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] オートファジーシステムの作動原理と多様性2018

    • Author(s)
      小松雅明
    • Organizer
      第91回日本生化学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] がんとオートファジー2018

    • Author(s)
      小松雅明
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Remarks] 順天堂大学医学部生理学第二講座

    • URL

      https://www.juntendo.ac.jp/graduate/laboratory/labo/kikan_saibou/

    • Related Report
      2019 Annual Research Report
  • [Remarks] 日本学術振興会 日中韓フォーサイト事業 オートファジー、代謝と神経変性疾患

    • URL

      https://www.med.niigata-u.ac.jp/bc1/A3/index.html

    • Related Report
      2019 Annual Research Report
  • [Remarks] 文部科学省 新学術領域研究 マルチモードオートファジー 多彩な経路と選択性が織り成す自己分解系の理解

    • URL

      http://proteolysis.jp/multimode_autophagy/

    • Related Report
      2019 Annual Research Report

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Published: 2018-05-01   Modified: 2024-03-26  

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