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

Cell Rep. 2019 Nov 5;29(6):1594-1609.e5. doi: 10.1016/j.celrep.2019.09.078.


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.

Keywords: RNA binding protein; Salmonella; hnRNP; inflammation; innate immune response; macrophage; phosphorylation; pre-mRNA splicing; spliceosome; toll-like receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Animals
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromatin Immunoprecipitation Sequencing
  • Exons
  • Gene Expression
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology
  • Gene Ontology
  • Heterogeneous-Nuclear Ribonucleoprotein Group M / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein Group M / immunology
  • Heterogeneous-Nuclear Ribonucleoprotein Group M / metabolism*
  • Humans
  • Immunity, Innate / genetics*
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Introns
  • Lipopolysaccharides / pharmacology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Macrophages / virology
  • Mice
  • Mutation
  • Phosphorylation
  • RAW 264.7 Cells
  • RNA Splicing / genetics
  • RNA Splicing / immunology*
  • RNA-Seq
  • Salmonella / physiology
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism


  • Chromatin
  • Heterogeneous-Nuclear Ribonucleoprotein Group M
  • Interleukin-6
  • Lipopolysaccharides
  • Toll-Like Receptor 4
  • interleukin-6, mouse