Abstract
Autophagy receptor p62/SQSTM1 promotes the assembly and removal of ubiquitylated proteins by forming p62 bodies and mediating their encapsulation in autophagosomes. Here we show that under nutrient-deficient conditions, cellular p62 specifically undergoes acetylation, which is required for the formation and subsequent autophagic clearance of p62 bodies. We identify K420 and K435 in the UBA domain as the main acetylation sites, and TIP60 and HDAC6 as the acetyltransferase and deacetylase. Mechanically, acetylation at both K420 and K435 sites enhances p62 binding to ubiquitin by disrupting UBA dimerization, while K435 acetylation also directly increases the UBA-ubiquitin affinity. Furthermore, we show that acetylation of p62 facilitates polyubiquitin chain-induced p62 phase separation. Our results suggest an essential role of p62 acetylation in the selective degradation of ubiquitylated proteins in cells under nutrient stress, by specifically regulating the assembly of p62 bodies.
Highlights
Autophagy receptor p62/SQSTM1 promotes the assembly and removal of ubiquitylated proteins by forming p62 bodies and mediating their encapsulation in autophagosomes
Autophagosomes capture protein aggregates through a panel of cargo receptor proteins. These cargo receptors use their ubiquitinassociated (UBA) domain to bind to ubiquitylated proteins, and their LC3-interaction region (LIR) to bind to Atg8/LC3 on autophagic membranes10–15. p62, the first autophagic cargo receptor identified in mammalian cells, plays a key role in mediating the formation and autophagic clearance of intracellular protein aggregates[13,16,17]
Previous studies have identified that acetylation plays important roles in autophagy regulation, and a number of autophagy related proteins (ATGs) undergo acetylation/deacetylation during cell starvation[28,29,30,31,32]
Summary
Autophagy receptor p62/SQSTM1 promotes the assembly and removal of ubiquitylated proteins by forming p62 bodies and mediating their encapsulation in autophagosomes. Our results suggest an essential role of p62 acetylation in the selective degradation of ubiquitylated proteins in cells under nutrient stress, by regulating the assembly of p62 bodies. Autophagic clearance of these p62-positive aggregates ensures that misfolded proteins are removed, and that the homeostatic level of p62 itself is preserved This is important because the accumulation of intracellular p62 is associated with the malignant transformation of autophagy-deficient cells[9,17]. It was recently suggested that like other intracellular membraneless compartments, the assembled p62-positive protein aggregates are liquid droplets formed by phase separation, which depends on the interaction between p62 and ubiquitin and can be regulated by posttranslational modification of p6223,24. We further show that the formation of p62 bodies, in addition to promoting their own degradation by selective autophagy, improves the survival of cells under nutrient starvation conditions
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