RNA binding as an emerging regulatory dimension in the type I IFN response

The type I interferon (IFN-I) response shapes the intracellular environment to suppress virus infection. Historically, this remodeling has been linked to the transcriptional induction of interferon-stimulated genes (ISGs). However, IFN-I-driven post-translational regulation of proteins already present in the cell remains relatively 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 both canonical antiviral proteins and non-canonical antiviral candidates, validated through a knockdown screen. 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 this phospho-driven regulation for MATR3. Altogether, our results characterize an important dimension of the cell’s antiviral program, in which the cellular RNA-bound proteome is remodeled by IFN-I.