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

Abstract

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. 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.

FGFR2-triggered autophagy and activation of Nrf-2 reduce breast cancer cell response to anti-ER drugs

“…In addition, p62 bodies contain p62-binding partners, such as ubiquitinated proteins, targeted for autophagic degradation. Ikeda et al have demonstrated that ULK1 phosphorylates Ser349 of p62 located in p62 bodies, which promotes the recruitment of Keap1, followed by activation of Nrf-2 [ 69 ]. Although we did not investigate the formation of p62 bodies, observed FGFR2-dependent phosphorylation of p62 and ULK1 suggest that this could be a potential mechanism of Nrf-2 activation.…”

White matter hyperintensity genetic risk factorTRIM47regulates autophagy in brain endothelial cells

“…Silencing Trim47 not only resulted in a significant upregulation of players (Atg7 Bcl2 and Gabarap) important for in autophagosome formation (Collier et al, 2021;Ma et al, 2013), but also increased the ECs with phosphorylation of ULK1 and p62 as well as vacuole formation. As ULK-mediates the phosphorylation of p62 (Ikeda et al, 2023), Trim47 is therefore pivotal to both early and later stage of autophagy (Egan et al, 2015). TRIM65, the other TRIM member at locus 17q25, is known to inhibit autophagy also by controlling Atg7 expression in lung cancer cells (Pan et al, 2019).…”

The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?

“…The death domain-associated protein (DAXX) and the autophagy receptor neighbor of BRCA1 gene 1 (NBR1) promote the oligomerization of p62 and its condensation into a liquid phase, facilitating the NRF2-mediated antioxidant response [174][175][176]. The formation of p62 bodies through liquid-liquid phase separation (LLPS) is regulated by unc-51-like kinase 1 (ULK1)-dependent phosphorylation of p62, which retains KEAP1 and activates NRF2 [177]. Conversely, the modulator of apoptosis 1 (MOAP-1) and the speckle-type BTB/POZ protein (SPOP) act as a negative regulator of NRF2 activation by disrupting the liquid phase condensation of p62 and SQSTM1 bodies [178,179].…”