Abstract 2721 Inhibition of SQSTM1/p62 oligomerization and Keap1 sequestration by the Cullin-3 adaptor SHKBP1

SQSTM1/p62 is a master regulator of the autophagic and ubiquitination pathways of protein degradation and the antioxidant response.p62 functions in these pathways via reversible assembly and sequestration of additional factors into cytoplasmic phase-separated structures termed p62 bodies.The physiological roles of p62 in these various pathways depends on numerous mechanisms for regulating p62 body formation and dynamics that are incompletely understood.Here, we identify a new mechanism for regulation of p62 oligomerization and incorporation into p62 bodies by SHKBP1, a Cullin-3 E3 ubiquitin ligase adaptor, that is independent of its potential functions in ubiquitination.We map a SHKBP1-p62 protein-protein interaction outside of p62 bodies that limits p62 assembly into p62 bodies and affects the antioxidant response by preventing sequestration and degradation of Keap1.These studies provide a non-ubiquitinationbased mechanism for an E3 ligase adaptor in regulating p62 phase separation and cellular responses to oxidative stress.