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

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K15594
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Kyoto 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
• Keywords: LUBAC / 細胞死 / 直鎖状ユビキチン鎖

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.

Free Research Field

分子生物学

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。