Identification of genes involved in the lysosomal degradation of aberrant membrane proteins at the endoplasmic reticulum

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K15026
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 43020:Structural biochemistry-related
• Research Institution: The University of Tokyo
• Principal Investigator: Hayashi Yuki 東京大学, 大学院薬学系研究科(薬学部), 特任研究員 (50879971)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: リソソーム / TOLLIP / 膜タンパク質 / ユビキチン / 小胞体ストレス / タンパク質品質管理

Outline of Final Research Achievements

MIsfolded membrane proteins in the endoplasmic reticulum (ER) can cause a variety of diseases. Since they are toxic, they are removed by selective degradation systems in the ER. In addition to the proteasome-dependent ERAD pathway, there is also a lysosome-dependent pathway for selective degradation of misfolded membrane proteins in the ER, but the detailed molecular mechanism of the lysosome pathway has not been clarified. In the present study, we have revealed the existence of a novel proteolytic pathway in which misfolded membrane proteins are selectively recognized by the adaptor protein TOLLIP, leading to lysosomal degradation. I have also elucidated the detailed molecular mechanism of this pathway, including the substrate recognition mechanism and the transport mechanism to lysosomes.

Free Research Field

タンパク質品質管理、小胞体ストレス

Academic Significance and Societal Importance of the Research Achievements

膜タンパク質のミスフォールディングは、筋萎縮性側索硬化症や遺伝性痙性対麻痺などの運動神経変性疾患をはじめ様々な疾患の原因となることが提唱されている。膜タンパク質の新規分解経路およびその重要因子を発見した本研究成果は、ミスフォールド膜タンパク質の選択的除去という、疾患の新たな治療戦略の創出に資するものであると考えられる。