A phosphorylation-driven functional switch in p62 bodies coordinates autophagic clearance of ubiquitinated proteins

p62/SQSTM1 self-assembles with polyubiquitin into liquid-like condensates (“p62 bodies”) that function as stress-signaling hubs and selective autophagy cargo. We show that TBK1-dependent phosphorylation at Ser403 acts as a tunable rheostat, inducing miniaturization and gelation of these condensates and licensing their rapid, piecemeal clearance. PP2A holoenzymes containing PPP2R5A/B/E, recruited via a KEAP1 bridge, counteract TBK1 by dephosphorylating Ser403. This phosphorylation within p62 bodies promotes a material transition from large, fluid droplets to compact, low-fluidity gels that efficiently capture LC3-positive isolation membranes and accelerate autophagic removal of ubiquitinated proteins. Homozygous p62S403E/S403E embryonic stem cells differentiate into post-mitotic neurons enriched in miniaturized, gel-like p62 bodies, suggesting that the same miniaturization–gelation mechanism maintains proteostasis in quiescent cells. Thus, a TBK1–PP2A switch at Ser403 regulates the material state of p62 condensates and serves as a central control point for p62-mediated proteostasis.