The splicing factor hnRNP M is a critical regulator of innate immune gene expression in macrophages

ABSTRACTWhile transcriptional control mechanisms of innate immune gene expression are 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 leads to hyperinduction of a unique regulon of inflammatory and antimicrobial genes, including IL6, Mx1, and Gbp5, following a variety of 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 activation of pathogen sensing cascades. 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.