Regulation of protein degradation by chemo-technology

2022 Fiscal Year Final Research Report

• Project Area: New frontier for ubiquitin biology driven by chemo-technologies
• Project/Area Number: 18H05500
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: The University of Tokyo
• Principal Investigator: Murata Shigeo 東京大学, 大学院薬学系研究科(薬学部), 教授 (20344070)
• Co-Investigator(Kenkyū-buntansha): 山野 晃史 東京医科歯科大学, 難治疾患研究所, 准教授 (30547526)
• Project Period (FY): 2018-06-29 – 2023-03-31
• Keywords: プロテアソーム / ユビキチン / 化合物 / PROTAC / オートファジー

Outline of Final Research Achievements

The results of using chemo-technology include: obtaining compounds that bind to the ubiquitin receptor of the proteasome, obtaining compounds that inhibit proteasome formation, identifying compounds that are synthetic lethal with proteasome inhibitors, creating PROTAC to artificially induce mitophagy, and obtaining monobody against optineurin, which led to the elucidation of new functions of optineurin. During these studies, we also discovered a new mechanism for regulating proteasome expression, liquid droplet formation as a new degradation mechanism by the proteasome, and the ubiquitination-deubiquitination cycle, which is important for ribosome recycling.

Free Research Field

タンパク質分解

Academic Significance and Societal Importance of the Research Achievements

これまでユビキチン化を介した標的タンパク質分解誘導方法は確立されていたが、今回の成果により、ユビキチン化を介さずに直接プロテアソームによる分解を誘導する基盤を作ることが出来た。また、ミトコンドリア分解誘導も実現でき、機能低下ミトコンドリアクリアランス不全に起因すると考えられる疾患の新しい治療戦略となる可能性がある。また、プロテアソームの制御機構が数多く明らかになり、プロテアソーム機能亢進や低下が関与する疾患群の治療標的を創出出来た。