Autophagy is induced by swine acute diarrhea syndrome coronavirus through the cellular IRE1-JNK-Beclin 1 signaling pathway after an interaction of viral membrane-associated papain-like protease and GRP78

Author summarySADS-CoV, a novel bat-origin pathogen belonging to the family Alphacoronavirus, was confirmed to be the aetiological agent that caused mass death of piglets in southern China in 2017. Strikingly, since the outbreak of SADS-CoV, multiple studies have highlighted the risk of cross-species transmission due to its broad cell tropism. A better understanding of the pathogenic mechanisms is expected to result in a more specific SADS-CoV prevention and control measures. As yet, the pathogenic mechanisms of SADS-CoV have so far not been characterized well. Here, we found that SADS-CoV infection induced a complete autophagy process in vitro and in vivo to facilitate virus propagation. Furthermore, it's indicated that ER stress and IRE1 pathway played indispensable functions in SADS-CoV-induced autophagy. Notably, we have provided first evidence that SADS-CoV PLP2-TMF451-L490 domain induced autophagy by interacting with substrate-binding domain of GRP78 to activate the IRE1-JNK-Beclin 1 signaling pathway. Overall, our study presented detailed mechanism of SADS-CoV-induced autophagy as well as a contribution for SADS-CoV pathogenesis. Autophagy plays an important role in the infectious processes of diverse pathogens. For instance, cellular autophagy could be harnessed by viruses to facilitate replication. However, it is still uncertain about the interplay of autophagy and swine acute diarrhea syndrome coronavirus (SADS-CoV) in cells. In this study, we reported that SADS-CoV infection could induce a complete autophagy process both in vitro and in vivo, and an inhibition of autophagy significantly decreased SADS-CoV production, thus suggesting that autophagy facilitated the replication of SADS-CoV. We found that ER stress and its downstream IRE1 pathway were indispensable in the processes of SADS-CoV-induced autophagy. We also demonstrated that IRE1-JNK-Beclin 1 signaling pathway, neither PERK-EIF2S1 nor ATF6 pathways, was essential during SADS-CoV-induced autophagy. Importantly, our work provided the first evidence that expression of SADS-CoV PLP2-TM protein induced autophagy through the IRE1-JNK-Beclin 1 signaling pathway. Furthermore, the interaction of viral PLP2-TMF451-L490 domain and substrate-binding domain of GRP78 was identified to activate the IRE1-JNK-Beclin 1 signaling pathway, and thus resulting in autophagy, and in turn, enhancing SADS-CoV replication. Collectively, these results not only showed that autophagy promoted SADS-CoV replication in cultured cells, but also revealed that the molecular mechanism underlying SADS-CoV-induced autophagy in cells.