Elucidation of the mechanisms of cell survival and death by linear ubiquitin chains

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K06635
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: Kyoto University
• Principal Investigator: Fujita Hiroaki 京都大学, 医学研究科, 助教 (90738006)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: LUBAC / 細胞死 / OTULIN / ユビキチン

Outline of Final Research Achievements

LUBAC ubiquitin (Ub) ligase, which specifically generates linear Ub chains, consists of catalytic center HOIP for linear Ub chains generation and accessory subunits HOIL-1L and SHARPIN, and is involved in NF-kB activation and cell death protection. Interestingly, HOIL-1L also has Ub ligase activity but its significance was unknown. We found that deletion of HOIL-1L Ub ligase activity enhances LUBAC activity and cell death was remarkably suppressed. On the other hand, deletion of OTULIN, which specifically cleaves linear Ub chains, increaced linear Ub chains in cells but cell death was promoted. We elucidated this mechanism and found that HOIL-1L attached mono-Ub into LUBAC and the Ub is linear ubiquitinated by LUBAC to suppress LUBAC function , and OTULIN cleaves the linear Ub chains of LUBAC to release linear ubiquitinated compromise LUBAC.

Free Research Field

細胞死

Academic Significance and Societal Importance of the Research Achievements

LUBACはNF-kBシグナルや細胞死抑制を担う非常に重要なタンパク質複合体である。特にNF-kBや細胞死はがんなどの様々な疾患と深い関係があるため、LUBAC、直鎖の制御機構を解明することは非常に重要である。
本研究ではLUBACの新たな制御様式を明らかにし、HOIL-1LのUbリガーゼ機能の欠失がLUBACの機能亢進に関与することを見出した。また細胞内直鎖が亢進するOTULIN欠損細胞では細胞死が亢進し、そのメカニズムとしてLUBAC自身の直鎖化が関与していることを見出した。これらはLUBACの新たな制御機構を明らかにするもので、非常に重要な意義を秘めている。