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

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