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

Author:

Ikeda Ryo12,Noshiro Daisuke3ORCID,Morishita Hideaki1ORCID,Takada Shuhei1,Kageyama Shun1,Fujioka Yuko3ORCID,Funakoshi Tomoko1,Komatsu‐Hirota Satoko1,Arai Ritsuko4,Ryzhii Elena4ORCID,Abe Manabu5,Koga Tomoaki6ORCID,Motohashi Hozumi7,Nakao Mitsuyoshi6ORCID,Sakimura Kenji5,Horii Arata2ORCID,Waguri Satoshi4ORCID,Ichimura Yoshinobu1ORCID,Noda Nobuo N3ORCID,Komatsu Masaaki1ORCID

Affiliation:

1. Department of Physiology Juntendo University Graduate School of Medicine Tokyo Japan

2. Department of Otolaryngology Head and Neck Surgery Niigata University Graduate School of Medical and Dental Sciences Niigata Japan

3. Institute for Genetic Medicine Hokkaido University Sapporo Japan

4. Department of Anatomy and Histology Fukushima Medical University School of Medicine Fukushima Japan

5. Department of Animal Model Development, Brain Research Institute Niigata University Niigata Japan

6. Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics Kumamoto University Kumamoto Japan

7. Department of Gene Expression Regulation, Institute of Development, Aging and Cancer Tohoku University Sendai Japan

Abstract

AbstractNRF2 is a transcription factor responsible for antioxidant stress responses that is usually regulated in a redox‐dependent manner. 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 p62 phosphorylation remain unclear. Here, we identify ULK1 as a kinase responsible for the phosphorylation of p62. ULK1 colocalizes with p62 bodies, directly interacting with p62. ULK1‐dependent phosphorylation of p62 allows KEAP1 to be retained within p62 bodies, thus activating NRF2. p62S351E/+ mice are phosphomimetic knock‐in mice in which Ser351, corresponding to human Ser349, is replaced by Glu. These mice, but not their phosphodefective p62S351A/S351A counterparts, exhibit NRF2 hyperactivation and growth retardation. This retardation is caused by malnutrition and dehydration due to obstruction of the esophagus and forestomach secondary to hyperkeratosis, a phenotype also observed in systemic Keap1‐knockout mice. Our results expand our understanding of the physiological importance of the redox‐independent NRF2 activation pathway and provide new insights into the role of phase separation in this process.

Funder

Japan Agency for Medical Research and Development

Japan Society for the Promotion of Science

Core Research for Evolutional Science and Technology

Takeda Science Foundation

Inamori Foundation

Publisher

Springer Science and Business Media LLC

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience

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