RLRs are important cytosolic PRRs that sense viral RNA before mounting a response leading to the activation of Type-I IFNs. Several viral infections induce epithelial-mesenchymal transition (EMT), even as its significance remains unclear. Here, we describe that EMT or EMT like process is a general response to viral infections. Our studies identify a previously unknown mechanism of regulation of an important EMT-TF Snail during RNA viral infections, and describe its possible implication. RNA viral infections, poly (I:C) transfection, and ectopic expression of RLR components induced Snail levels, indicating that RLR pathway could regulate its expression. Detailed examination using MAVS-KO cells established that MAVS is essential in this regulation. We identified two ISREs in
SNAI1
promoter region and demonstrated that they are important in its transcriptional activation by phosphorylated IRF3. Increasing the levels of Snail activated RLR pathway and dramatically limited replication of RNA viruses DENV, JEV and VSV, pointing to their antiviral functions. Knock-down of Snail resulted in considerable increase in JEV titer, validating its antiviral functions. Finally, TGF-β mediated
IFNB
activation was dependent on Snail levels, confirming its important role in Type-I IFN activation. Thus, EMT-TF Snail is transcriptionally co-regulated with Type-I IFN by RLRs and in turn promotes RLR pathway, further strengthening the antiviral state in the cell. Our work identified an interesting mechanism of regulation of Snail that demonstrates potential co-regulation of multiple innate antiviral pathways triggered by RLRs. Identification of antiviral functions of Snail also provides an opportunity to expand the sphere of RLR signaling.
IMPORTANCE
RLRs sense viral genomic RNA or the dsRNA intermediates and trigger the activation of Type I IFNs. Snail transcription factor, commonly associated with epithelial-mesenchymal transition, has been reported to facilitate EMT in several viral infections. Much of these reports come from oncoviruses, leading to the speculation that EMT induced during infection is an important factor in the oncogenesis triggered by these infections. However, our studies reveal that EMT or EMT like processes during viral infections have important functions in antiviral response. We have characterized a new mechanism of transcriptional regulation of Snail by IRF3 through ISRE in their promoters and this finding could have importance in non-viral contexts as well. We also identify that EMT-TF Snail promotes antiviral status of the infected cells through RLR pathway. This work characterizes a new regulatory mechanism of activation of Snail and establishes its unidentified function in antiviral response.
Retinoic Acid Inducible Gene-I like Receptors Activate Snail and Slug to Limit RNA Viral Infections
