Phosphorylation of phase-separated p62 bodies by ULK1 activates a redox-independent stress response

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K06644
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: Juntendo University
• Principal Investigator: Ichimura Yoshinobu 順天堂大学, 医学部, 先任准教授 (80400993)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 選択的オートファジー / p62 / ULK1 / リン酸化 / p62-KEAP1-NRF2経路

Outline of Final Research Achievements

p62 bodies formed by liquid-liquid phase separation contain Ser349-phosphorylated p62, which participates in the redox-independent activation of NRF2. However, the regulatory mechanism and physiological significance of phosphorylation remain unclear. Herein, we identify ULK1 as a kinase responsible for phosphorylation of p62. ULK1 co-localizes with p62 bodies, and directly interacts with p62. p62S351E/+ mice are phosphomimetic knock-in mice in which Ser351 corresponding to human Ser349 is replaced by Glu. These mice, but not phosphodefective p62S351A/S351A mice, exhibit NRF2 hyperactivation and growth retardation, the latter caused by malnutrition and dehydration due to obstruction of the esophagus and forestomach secondary to hyperkeratosis. Our results expand our understanding of the physiological importance of the redox-independent NRF2 activation pathway and provide new insight into the role of phase separation in this process.

Free Research Field

オートファジー

Academic Significance and Societal Importance of the Research Achievements

本研究成果は細胞のストレス応答機構や液―液相分離の生理的役割について新たな知見を与えるものである。p62顆粒は肝疾患、神経変性疾患の病変細胞や肝細胞がんの病変部位で過剰に蓄積することが知られており、これら病態においてレドックス非依存性ストレス応答が調整不全となっていることが強く疑われる。本研究で得られた知見をもとに、より詳細な解析を進めることで、p62顆粒が関与する病態発症機序の解明が期待される。