The production of functionally diverse protein isoforms via alternative splicing is also known to influence innate immune responses. Like-wise, computational analyses of human primary macrophages reveal a robust increase in mRNA isoform diversity and a global preference for exon inclusion following lipopolysaccharide (LPS) treatment or Salmonella enterica serovar Typhimurium infection ( Pai et al., 2016). For example, when primary mouse macrophages are treated with a Toll-like receptor 4 (TLR4) agonist, individual transcripts show significant variation in the time it takes for them to be fully spliced, with some pre-mRNAs remaining unprocessed for hours after transcriptional activation ( Bhatt et al., 2012 Pandya-Jones et al., 2013). Although innate immune gene expression is mostly studied in the context of transcriptional activation, multiple lines of evidence support a crucial role for pre-mRNA splicing regulation in shaping the macrophage transcriptome. When innate immune cells like macrophages sense pathogens, they undergo a massive reprogramming of gene expression. 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. 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. Loss of hnRNP M led to hyperinduction of a unique regulon of inflammatory and antimicrobial genes following diverse innate immune stimuli. 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. 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.
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