The Splicing Factor hnRNP M Is a Critical Regulator of Innate Immune Gene Expression in Macrophages

While transcriptional control of innate immune gene expression is well characterized, almost nothing is known about how pre-mRNA splicing decisions influence, or are influenced by, macrophage activation. Here, we demonstrate that the splicing factor hnRNP M is a critical repressor of innate immune gene expression and that its function is regulated by pathogen sensing cascades. Loss of hnRNP M led to hyperinduction of a unique regulon of inflammatory and antimicrobial genes following diverse innate immune stimuli. While mutating specific serines on hnRNP M had little effect on its ability to control pre-mRNA splicing or transcript levels of housekeeping genes in resting macrophages, it greatly impacted the protein’s ability to dampen induction of specific innate immune transcripts following pathogen sensing. These data reveal a previously unappreciated role for pattern recognition receptor signaling in controlling splicing factor phosphorylation and establish pre-mRNA splicing as a critical regulatory node in defining innate immune outcomes. [Display omitted] •hnRNP M represses a cohort of innate immune transcripts in macrophages•hnRNP M associates with the IL6 genomic locus to co-transcriptionally repress splicing•Following infection, phosphorylation of hnRNP M at S574 can relieve this repression•Loss of hnRNP M enhances macrophages’ ability to control viral infection West et al. report that hnRNP M represses expression of a cohort of innate immune transcripts in infected macrophages. IL6 splicing repression is relieved when hnRNP M is phosphorylated at specific residues, demonstrating that post-translational modification of splicing factors downstream of pathogen sensing can control maturation of innate immune mRNAs.