Analysis of the molecular pathogenesis of the selective autophagy substrate p62/SQSTM1 droplet

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K06549
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: Juntendo University
• Principal Investigator: Kageyama Shun 順天堂大学, 医学部, 助教 (30624225)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: オートファジー / p62-KEAP1-NRF2 / 酸化ストレス / リン酸化 / 液－液相分離 / 液滴

Outline of Final Research Achievements

The mechanism of selective autophagic degradation of p62 protein, which forms droplets by liquid-liquid phase separation, and the molecular pathogenesis of disease-related point mutations were unknown. Here, we found that p62 droplets serve as a scaffold for autophagosome formation and are selectively degraded via interaction with LC3/GABARAP proteins localized on the autophagosome membrane. We also found that the properties of p62 droplets are regulated by post-translational modifications and that disease-associated point mutations result in qualitative changes in p62 droplets.

Free Research Field

タンパク質分解

Academic Significance and Societal Importance of the Research Achievements

神経変性疾患などで確認される封入体は生化学的機能を消失した液滴の凝集化体であると考えられるようになっており、液滴制御機構の解明は急務である。本研究は基礎研究領域のみならず臨床や創薬への応用まで大きく波及効果をもたらし、革新的・創造的な学術研究の発展に寄与すると期待される。