Cytoplasmic cargo receptor p62 inhibits avibirnavirus replication by mediating autophagic degradation of viral protein VP2.

Selective autophagy regulates the degradation of cytoplasmic cargos, such as damaged organelles, invading pathogens, and aggregated proteins. Furthermore, autophagy is capable of degrading avibirnavirus, but the mechanism responsible for this process is unclear. Here, we show that autophagy cargo receptor p62 regulates the degradation of the avibirnavirus capsid protein VP2. Binding of p62 to VP2 enhance autophagic induction and promotes autophagic degradation of viral protein VP2. Further study showed that the interaction of p62 with viral protein VP2 is dependent on ubiquitination at the K411 site of VP2 and the ubiquitin-associated domain of p62. Mutation analysis showed that the K411R mutation of viral protein VP2 prohibits its p62-mediated degradation. Consistently, p62 lacking the ubiquitin-associated domain or LC3-interacting region no longer promoted degradation of VP2. Virus production revealed that knockout of p62 but not overexpression of p62 promotes the replication of avibirnavirus. Collectively, our findings suggest that p62 mediates selective autophagic degradation of avibirnavirus protein VP2 in an ubiquitin-dependent manner and is an inhibitor of avibirnavirus replication.ImportanceAvibirnavirus causes severe immunosuppression and mortality in young chickens. VP2, capsid protein of avibirnavirus, is responsible for virus assembly, maturation and replication. Previous study showed that avibirnavirus particles could be engulfed into autophaogosome and degradation took apart. Selective autophagy is a highly specific and regulated degradation pathway for the clearance of damaged or unwanted cytosolic components and superfluous organelles as well as invading microbes. However, whether and how selective autophagy removes avibirnavirus capsids is largely unknown. Here, we have shown that selective autophagy specifically clears ubiquitinated avibirnavirus protein VP2 by p62 recognition and that p62 is an inhibitor of avibirnavirus replication, highlighting the role of p62 as a potential drug target for mediating the removal of ubiquitinated virus components from cells.