CoV nsp15 has EndoU catalytic activity that was initially thought to play a vital role in virus replication. However, the catalytic-defective EndoU of MHV shows only a subtle defect in viral replication compared to WT virus in fibroblasts [215]. Similar results are found for the nsp15 mutants of SARS-CoV and HCoV-229E [216]. These findings suggest that the EndoU activity of nsp15 is not required for RNA synthesis. Recently, nsp15 has been demonstrated to act as a new IFN antagonist of CoVs [117,118,217]. Recent reports indicate that CoVs’ EndoU activity is essential for prevention of RNA recognition by MDA5, protein kinase R (PKR), and OAS/RNAse L system [118]. PKR and OAS/RNAse L recognize and destroy foreign RNA in the cytosol to defend viral infections. To counteract the function of PKR and OAS/RNAse L, the virus hides or modifies its viral RNA, to avoid the exposure of viral RNA to these molecules. In all CoVs, the EndoU catalytic domain in nsp15 is highly conserved. PEDV EndoU activity has been indicated as having an antagonistic effect on IFN signaling [135]. The EndoU activity of PEDV nsp15 not only inhibits the type I IFN response in porcine macrophages, but also antagonizes the type III IFN response in porcine epithelial cells. The replication of EndoU-mutant PEDV (icPEDV-EnUmt) is considerably impaired in porcine epithelial cells compared to the wild type PEDV (icPEDV-wt). The icPEDV-EnUmt clearly induces early and robust type I and type III IFNs production, as well as ISGs’ expression compared with that induced by icPEDV-wt. The EndoU-deficient PEDV infected animals also show reduced viral shedding and mortality. These results indicate that the EndoU activity of PEDV nsp15 plays a vital role in evading host antiviral innate immunity (Figure 2) [135].