PDCoV nsp14 interferes with the interferon pathway by degradin MAVS, MyD88, and TRAF3 proteins via the autophagy and proteasome pathways

Porcine deltacoronavirus (PDCoV) is a newly identified pathogen that can potentially undergo cross-species transmission to threaten the safety of swine and humans. The mechanism by which PDCoV nonstructural protein 14 (nsp14) inhibits the expression of IFN-β is unknown. In this study, we showed that PDCoV nsp14 degrades the MAVS, MyD88 and TRAF3 proteins in host cells by proteasomal and autophagy pathways. PDCoV nsp14 recruits the E3 ubiquitin ligase MARCH8 for catalyzing MAVS, MyD88 and TRAF3 protein ubiquitination. These proteins were recognized and transported to lysosomes by the cargo receptor NDP52 for degradation to inhibit the expression of IFN-β. Furthermore, MAVS, MyD88 and TRAF3 were also found to degrade PDCoV nsp14 by selective autophagy. These results reveal the dual function of selective autophagy in the PDCoV nsp14 and host proteins, which can promote the ubiquitination of viral particles and host antiviral proteins to degrade them both for regulating the relationship between virus infection and host innate immunity.