Antiviral Activity of ISG15 Against Porcine Deltacoronavirus Replication in IPEC-J2 by ISGylating PCNA

In this study, we identified known and novel candidate ISG15-binding proteins and analyzed the protein complexes by affinity pulldown and quantitative LC-MS/MS analyses in an IPEC-J2 cell line stably expressing ISG15 during PDCoV infection. We demonstrated that ISG15 conjugated to PCNA via specific Lys residues, which is the critical host factor for PDCoV replication, thereby suppressing viral propagation. We obtained evidence suggesting that HERC5 E3 ligase specifically promotes PCNA ISGylation and USP18 served as an ISG15-de-conjugating enzyme. We believe that our study makes a significant contribution to the literature because it is in advances our understanding of the function of ISG15 with expanding the physical and functional candidate protein interaction networks of ISG15 and suggesting ISGylation of PCNA plays a crucial role in PDCoV replication.