)Regulation of protein degradation by proteasome-interacting ubiquitin ligases

2023 Fiscal Year Final Research Report

• Project/Area Number: 20H03214
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: TSUCHIYA Hikaru 公益財団法人東京都医学総合研究所, 基礎医科学研究分野, 主任研究員 (90760132)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: タンパク質分解 / ユビキチン

Outline of Final Research Achievements

The ubiquitin-proteasome system regulates various biological phenomena by performing selective proteolysis. Ubiquitinated substrates are directly recognized and degraded by the proteasome directly. However, it is gradually becoming clear that various interacting proteins that interact with the proteasome in a transient and sub-stoichiometric manner can positively or negatively regulate the proteasomal degradation cycle. We found that several disease-related ubiquitin ligases, such as the ubiquitin ligase E6AP (responsible for Angelman syndrome, autism, and cervical cancer), interact with the proteasome through comprehensive analysis of proteins interacting with the proteasome. They found that E6AP interacts with a domain of unknown function of Rpn10 (ubiquitin receptor) and is involved in the degradation of abnormal proteins. Furthermore, we found that the ubiquitin ligase UBE3B also interacts with the novel binding domain of Rpn10.

Free Research Field

タンパク質分解

Academic Significance and Societal Importance of the Research Achievements

E6APの変異がアンジェルマン症候群（重度の発育・精神遅滞疾患）の原因遺伝子として30年以上解析されているが、その機能に関しては殆どわかっていない。本研究はプロテアソームとの相互作用の観点から疾患性のユビキチンリガーゼの機能を解析するものであり新たな治療薬開発の分子基盤になることが期待される。また、これまでプロテアソームが直接ユビキチン化基質を認識するという従来のモデルに対し、「ユビキチンリガーゼによりプロテアソーム上で基質の分解活性が制御される」というユビキチン・プロテアソーム系の基本的な作動機構について新規に提案している点で学術的意義が高い。