ZNF219 inhibits porcine epidemic diarrhea virus by degrading viral S2 protein

Since its discovery, porcine epidemic diarrhea virus (PEDV) has significantly affected the agricultural economy worldwide. The available commercialized coronavirus vaccines cannot adequately control emerging strains. Therefore, investigating the correlation between viruses and antiviral host factors is necessary. In this study, we showed that zinc finger protein 219 (ZNF219) was upregulated by viral nonstructural protein 12 (nsp12) upon PEDV challenge. Moreover, ZNF219 inhibited the replication of PEDV through selective autophagic degradation of the PEDV S2 protein. ZNF219 recruited TRAF6, the ubiquitin E3 ligase, to ubiquitinate the PEDV S2 protein. After recognition, the ubiquitinated PEDV S2 protein was delivered to autolysosomes via the cargo receptor p62 for degradation by autophagy, thus inhibiting the proliferation of PEDV. To summarize, after sensing PEDV infection by recognizing the viral nsp12 protein, host cells upregulated the intracellular expression of ZNF219, which degraded the viral S2 protein by activating autophagy, thus suppressing viral replication. Our study revealed a novel antiviral mechanism involving ZNF219 and provided a novel target for preventing and treating PEDV. • PEDV nsp12 upregulates ZNF219 expression in PEDV infection. • ZNF219 interacts with the PEDV S2, M, and N proteins. • ZNF219 ubiquitinates the PEDV S2 protein by recruiting TRAF6. • ZNF219 degrades the PEDV S2 protein via the ZNF219-TRAF6-p62-autophagy pathway.