Retinoic acid Inducible Gene-I like Receptors Activate Snail and Slug to Limit RNA Viral Infections

Several viruses have been reported to induce EMT in culture models, with their functional relevance remaining under-studied. Here, by linking the activation of EMT-TFs Snail and Slug by RLRs and the widespread observation of EMT by RNA viruses, we propose that EMT is a general cellular response in epithelial cells to RNA viral infections. Using viral genomic RNA and dsRNA analog transfection models, we identify that viral RNAs are strong inducers of EMT-TFs Snail and Slug, which required the phosphorylation of IRF3 by RLRs. Importantly, the ISRE elements that we identified in the SNAI1 promoter were critical for this transcriptional activation. Over-expressing Snail or Slug significantly elevated the RLR levels, TBK1 and STAT1 phosphorylations and several ISGs, providing the cells with higher refractoriness to RNA viruses. This antiviral property of these EMT-TFs is indicative of their unidentified roles in innate immune response, which position them as potential antiviral regulators. Together, our studies demonstrate a previously unidentified mechanism of activation of Snail and Slug and establish a new paradigm for their functions in innate immunity.