Cell Biology of Proteasomes

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H00997
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 44:Biology at cellular to organismal levels, and related fields
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: TANAKA Keiji 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, 理事長 (10108871)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: プロテアソーム / ユビキチン / 細胞内タンパク質分解 / 液―液相分離 / 神経変性疾患 / 遺伝学的解析 / ストレス応答 / PROTACs

Outline of Final Research Achievements

In the selective proteolytic pathway by proteasomes, there are many unresolved issues, such as the use of higher-order structural information of ubiquitin modifications presented to target proteins (referred as ubiquitin code) and their discriminating molecules (referred as decoders), as well as the action and regulatory mechanisms of proteasomes. In this study, we aimed to elucidate the pathology and physiology of the proteasome at in vivo level by creating mice with functionally weak activity of proteasomes and to provide a molecular basis for proteasome drug discovery. We successfully established a new concept of liquid-liquid phase separation-dependent proteolysis mechanism responsible for environmental stresses. Moreover, we have also clarified the involvement of ubiquitin-branched chains and identification of their generating enzymes in the selective proteolysis inducer PROTACs, opening a new possibility for next-generation drug discovery research.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

近年、タンパク質分解の細胞内機構と病態生理研究は飛躍的に進展しつつあり、本研究では、その中核酵素であるプロテアソームの基礎研究から病態解明及び創薬研究への道を開拓した。プロテアソームの変異疾患が相次いで報告されているが、それらを検証するための機能減弱マウスの作出に世界で初めて成功した。またプロテアソームが環境ストレスに応答して可逆的に相分離しタンパク質の迅速分解に貢献していることの発見は、神経変性疾患における易凝集性タンパク質の異常による封入体形成機序解明のヒントになる。標的タンパク質分解誘導剤PROTACsにおけるユビキチン分岐鎖と創成酵素の発見は、次世代創薬研究への波及効果が期待できる。