Swine acute diarrhea syndrome coronavirus Nsp1 suppresses IFN-[lambda]1 production by degrading IRF1 via ubiquitin-proteasome pathway

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel porcine enteric coronavirus that causes acute watery diarrhea, vomiting, and dehydration in newborn piglets. The type III interferon (IFN-[lambda]) response serves as the primary defense against viruses that replicate in intestinal epithelial cells. However, there is currently no information available on how SADS-CoV modulates the production of IFN-[lambda]. In this study, we utilized IPI-FX cells (a cell line of porcine ileum epithelium) as an in vitro model to investigate the potential immune evasion strategies employed by SADS-CoV against the IFN-[lambda] response. Our results showed that SADS-CoV infection suppressed the production of IFN-[lambda]1 induced by poly(I:C). Through screening SADS-CoV-encoded proteins, nsp1, nsp5, nsp10, nsp12, nsp16, E, S1, and S2 were identified as antagonists of IFN-[lambda]1 production. Specifically, SADS-CoV nsp1 impeded the activation of the IFN-[lambda]1 promoter mediated by MAVS, TBK1, IKK[epsilon], and IRF1. Both SADS-CoV and nsp1 obstructed poly(I:C)-induced nuclear translocation of IRF1. Moreover, SADS-CoV nsp1 degraded IRF1 via the ubiquitin-mediated proteasome pathway without interacting with it. Overall, our study provides the first evidence that SADS-CoV inhibits the type III IFN response, shedding light on the molecular mechanisms employed by SADS-CoV to evade the host immune response. Keywords: Swine acute diarrhea syndrome coronavirus, Nsp1, IFN-[lambda], IRF1, innate immune evasion