期刊
EMBO JOURNAL
卷 42, 期 14, 页码 -出版社
WILEY
DOI: 10.15252/embj.2022113349
关键词
KEAP1; liquid-liquid phase separation; NRF2; p62; SQSTM1; ULK1
ULK1 is a kinase responsible for the phosphorylation of p62, which activates NRF2. p62(S351E/+) mice, with phosphorylation-mimicking mutation, exhibit NRF2 hyperactivation and growth retardation.
NRF2 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. p62(S351E/+) mice are phosphomimetic knock-in mice in which Ser351, corresponding to human Ser349, is replaced by Glu. These mice, but not their phosphodefective p62(S351A/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.
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