RNA binding regulation is a new dimension in the type I IFN response

The type I interferon (IFN-I) response shapes the intracellular environment to supress virus infection. Historically, this remodelling has been linked to the transcriptional induction of interferon stimulated genes (ISGs). However, whether IFN-I alters the activity of proteins already present in the cell remains largely unexplored. Here, we profiled the activity of cellular RNA-binding proteins (RBPs), which are key players in antiviral immunity. Using RNA interactome capture (RIC), we identified hundreds of RBPs whose association with RNA is regulated by IFN-I (IR-RBPs). Among these IR-RBPs are known antiviral proteins, as well as novel antiviral candidates, identified through functional assays. By modifying RIC to study IR-RBPs' phosphorylation states, we identified several putative instances of IFN-I-driven phospho-regulation of RNA binding. We experimentally confirmed that MATR3's IFN-regulated S188 phosphosite modulates its RNA-binding activity, speaking to an exciting new layer of regulation. Altogether, our results reveal a new dimension of the cell's antiviral programme, in which the cellular RNA-bound proteome is remodelled by IFN-I. Overall design: iCLIP of WT MATR3-GFP and two mutants, S118A and S118D, in mock conditions. All samples were generated as biological triplicates. Size matched input samples derived from the parental HEK293 FITR line were used as a control for all three lines.