Fine morphology and molecular basis of liquid-liquid phase separation caused by the p62 mutation

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03415
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48010:Anatomy-related
• Research Institution: Fukushima Medical University
• Principal Investigator: Waguri Satoshi 福島県立医科大学, 医学部, 教授 (30244908)
• Co-Investigator(Kenkyū-buntansha): 田村 直輝 福島県立医科大学, 医学部, 講師 (70745992)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: p62液滴 / SQSTM1 / 液－液相分離 / ストレス顆粒 / 高浸透圧ストレス / 選択的オートファジー / Keap1

Outline of Final Research Achievements

To investigate the physiological significance of p62 droplets, the influence of disease-related genetic mutations in p62 on droplet structure was investigated. However, as a similar study was reported by others, the research plan was changed and detailed analyses of p62-droplets in various experimental systems were carried out. We found that p62-droplets and stress granules induced under hyperosmotic stress showed distinct behavior and fine structures. We also found molecules that undergo autophagy degradation via p62-droplets. In addition, inhibition of LC3-dependent selective autophagy in hepatocytes resulted in the formation of p62-droplets with numerous small vesicles, where Keap1 was also localized. Together with other results, the p62-droplets serve as a platform for both autophagy and stress response signaling.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

p62の遺伝子変異や封入体形成は、神経変性疾患、非アルコール性脂肪肝炎、肝細胞癌等で報告されている。これら封入体の形成は液－液相分離から始まると考えられるが、その病態生理学的な意義は不明であった。また、LC3に依存した選択的オートファジーの基質分解機序は明確ではなかった。今回、p62液滴の形成が選択的オートファジーの重要なプロセスを成すこと、その発動がストレス応答に直接関連していることを示した。本成果は、選択的オートファジーの新たな意義の解明につながると共に、p62液滴形成を制御することが上記疾患の病態の理解と、治療開発の糸口に繋がることを意味する。