Coronavirus NSP5 protease cleaves CCDC50 to evade antiviral autophagy

Selective macroautophagy/autophagy is a critical component of innate antiviral defense, relying on selective autophagy receptors to recognize viral cargo and deliver it for lysosomal degradation. In our recent study, we demonstrated that porcine deltacoronavirus (PDCoV) evades this pathway through its NSP5 protease. We uncovered a previously unrecognized antiviral function of the selective autophagy receptor CCDC50, which recognizes K63-linked polyubiquitinated PDCoV envelope (E) protein at lysine 72 and mediates its autophagic degradation, thereby restricting viral replication. This antiviral mechanism operates independently of the canonical receptors SQSTM1/p62 and NBR1. We further demonstrate that PDCoV NSP5 cleaves CCDC50 at glutamine 171, a conserved cleavage site also targeted by NSP5 orthologs from porcine epidemic diarrhea virus/PEDV, transmissible gastroenteritis virus/TGEV, and SARS-CoV-2. This cleavage disrupts the interaction of CCDC50 with ubiquitin and MAP1LC3/LC3, thereby impairing autophagic degradation of the E protein. Collectively, these findings establish CCDC50 as a selective autophagy receptor with antiviral activity against coronaviruses and reveal that coronavirus NSP5 promotes infection by proteolytically dismantling receptor-mediated antiviral autophagy.