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Elucidation of cell death regulation mechanisms and physiological significance by HOIL-1L

Research Project

Project/Area Number 17K15594
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field General medical chemistry
Research InstitutionKyoto University

Principal Investigator

Fujita Hiroaki  京都大学, 医学研究科, 助教 (90738006)

Project Period (FY) 2017-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
KeywordsLUBAC / 細胞死 / 直鎖状ユビキチン鎖 / ユビキチン / 直鎖状ポリユビキチン鎖 / HOIL-1L
Outline of Final Research Achievements

LUBAC is a only ubiquitin ligase that specifically generates linear ubiquitin chains. LUBAC is composed of catalytic subunit HOIP and accessory subunits HOIL-1L and SHARPIN. LUBAC is involved in NF-kappaB activation and cell death regulation. Dysregulation of LUBAC causes several diseases such as cancer and inflammatory disease. Here, we seeked the regions of LUBAC that is involved in cell death regulation, and identified HOIL-1L is essential for cell death regulation. We also generated mice in which regions of HOIL-1L, which are important for cell death regulation, were mutated to elucidate physiological role of cell death control by HOIL-1L.

Academic Significance and Societal Importance of the Research Achievements

HOIL-1Lの細胞死制御メカニズムを解明する過程でHOIL-1L UBLドメインがHOIPの安定性、細胞死制御に必須の役割を担っていることを見出した。またLUBACが三者複合体で初めて安定化するメカニズムを明らかにし、これまで知られていなかった、HOIL-1L/SHARPINの結合がLUBACの安定性に重要な役割を担っていることを明らかにした。また、同結合を阻害するペプチドを作成したところ、LUBACを不安定化し、がん細胞を死滅させることができた。上記に加え、HOIL-1LのRBRドメインがLUBACの直鎖形成を抑制することで細胞死を調節していることを見出した。

Report

(3 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • Research Products

    (3 results)

All 2019 2018

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (2 results) (of which Invited: 1 results)

  • [Journal Article] Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC Stabilization2018

    • Author(s)
      Fujita Hiroaki、Tokunaga Akira、Shimizu Satoshi、Whiting Amanda L.、Aguilar-Alonso Francisco、Takagi Kenji、Walinda Erik、Sasaki Yoshiteru、Shimokawa Taketo、Mizushima Tsunehiro、Ohki Izuru、Ariyoshi Mariko、Tochio Hidehito、Bernal Federico、Shirakawa Masahiro、Iwai Kazuhiro
    • Journal Title

      Cell Reports

      Volume: 23 Issue: 4 Pages: 1192-1204

    • DOI

      10.1016/j.celrep.2018.03.112

    • NAID

      120006460107

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] LUBAC安定化機構の解明と応用2019

    • Author(s)
      藤田宏明
    • Organizer
      医科研若手シンポジウム
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Crystal structure of trimeric LUBAC reveals essential role of a novel HOIL-1L-SHARPIN interaction in LUBAC formation and function2018

    • Author(s)
      Fujita, H., Tokunaga A., Iwai, K.
    • Organizer
      第40回日本分子生物学会 シンポジウム
    • Related Report
      2018 Annual Research Report

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Published: 2017-04-28   Modified: 2021-03-11  

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