PDCoV NSP5 cleaves the selective autophagy receptor CCDC50 to disrupt autophagic degradation of the viral envelope protein

Selective autophagy is a critical host defense mechanism that eliminates viral components through lysosomal degradation during coronavirus infection. Coronaviruses (CoVs), however, deploy countermeasures that disrupt this process, and several underlying mechanisms remain unresolved. Here, we identify the autophagy receptor CCDC50 as a substrate of the coronavirus-encoded NSP5 protease. During porcine deltacoronavirus (PDCoV) infection, NSP5 cleaves CCDC50 at glutamine 171 (Q171), a conserved site also processed by NSP5 from PEDV, TGEV, and SARS-CoV-2. Functionally, CCDC50 restricts PDCoV replication by recognizing the envelope (E) protein when it is modified with K63-linked polyubiquitin at lysine 72 (K72) and routing it for autophagic degradation, independently of canonical receptors such as SQSTM1/p62 and NBR1. NSP5-mediated cleavage disrupts CCDC50 interaction with LC3 and ubiquitin, reduces its capacity to target E for degradation, and thereby compromises its antiviral activity. Taken together, our study identifies CCDC50 as a previously uncharacterized antiviral autophagy receptor in coronavirus infection and reveals that PDCoV circumvents this defense through NSP5-mediated cleavage to promote productive infection.IMPORTANCEIn our study, we investigated the interplay between host autophagy pathways and coronavirus infection. We identified the selective autophagy receptor CCDC50 as a potent antiviral factor that suppresses porcine deltacoronavirus (PDCoV) replication. We demonstrated that CCDC50 specifically recognizes the viral envelope (E) protein and targets it for autophagic degradation, thereby restricting the virus. However, we also uncovered a sophisticated viral escape mechanism. We found that PDCoV's main protease, NSP5, cleaves CCDC50 directly at a specific residue, glutamine 171. This proteolytic event impairs the ability of CCDC50 to interact with ubiquitin and the core autophagy machinery, effectively neutralizing its antiviral function and promoting viral replication. Significantly, we determined this to be a highly conserved strategy among coronaviruses. Our findings show that the NSP5 proteases of other divergent coronaviruses, including PEDV, TGEV, and even SARS-CoV-2, all target the same conserved site in CCDC50. These results reveal a common mechanism that coronaviruses use to subvert selective host autophagy.