Infection control via activating linear ubiquitin chain formation

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16144
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Kyoto University
• Principal Investigator: Fuseya Yasuhiro 京都大学, 医学研究科, 特定助教 (60866523)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: LUBAC / HOIL-1L / 直鎖状ユビキチン鎖 / ユビキチン / サルモネラ / 細胞死

Outline of Final Research Achievements

LUBAC, which specifically generates linear ubiquitin chains, consists of HOIP, SHARPIN, and HOIL-1L. LUBAC contains two distinct ubiquitin ligases, one each in HOIP and HOIL-1L, and HOIP specifically generates linear chains as the main catalytic center of LUBAC. The physiological significance of the second ligase of HOIL-1L within LUBAC remained elusive. We revealed that HOIL-1L ligase activity down-regulated LUBAC physiological functions via monoubiquitination of LUBAC subunits. We also found that introduction of a HOIL-1L mutant lacking E3 activity protected cells from Salmonella infection by augmenting linear ubiquitination by LUBAC.

Free Research Field

医化学一般

Academic Significance and Societal Importance of the Research Achievements

免疫応答や細胞死制御に加え、感染防御に重要な役割を果たす複合体ユビキチンリガーゼLUBACの新規活性制御機構を明らかにした。HOIL-1Lのユビキチンリガーゼ活性はLUBACの直鎖状ユビキチン鎖生成能を抑制しており、HOIL-1Lのリガーゼ活性を阻害すれば、LUBACの機能を増強できることを見出した。まら細胞レベルでHOIL-1Lのリガーゼ活性阻害によるLUBACの機能亢進は、サルモネラ菌感染を抑制することを見出した。