Diverging mRNA and Protein Networks in Activated Microglia Reveal SRSF3 Suppresses Translation of Highly Upregulated Innate Immune Transcripts

Cell Rep. 2017 Dec 12;21(11):3220-3233. doi: 10.1016/j.celrep.2017.11.058.


Uncontrolled microglial activation may lead to the development of inflammation-induced brain damage. Here, we uncover a ribosome-based mechanism/checkpoint involved in control of the innate immune response and microglial activation. Using an in vivo model system for analysis of the dynamic translational state of microglial ribosomes, with mRNAs as input and newly synthesized peptides as an output, we find a marked dissociation of microglia mRNA and protein networks following innate immune challenge. Highly upregulated and ribosome-associated mRNAs were not translated, resulting in two distinct microglial molecular signatures, a highly specialized pro-inflammatory mRNA signature and an immunomodulatory/homeostatic protein signature. We find that this is due to specific translational suppression of highly expressed mRNAs through a 3' UTR-mediated mechanism involving the RNA-binding protein SRSF3. This discovery suggests avenues for therapeutic modulation of innate immune response in resident microglia.

Keywords: innate immune response; microglia; microglia proteomics; translatome profiling.

MeSH terms

  • Animals
  • Binding Sites
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / immunology
  • Cerebral Cortex / pathology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Regulatory Networks / immunology
  • Immunity, Innate / drug effects
  • Lipopolysaccharides / pharmacology*
  • Male
  • Mice
  • Mice, Transgenic
  • Microglia / drug effects*
  • Microglia / immunology
  • Microglia / pathology
  • Protein Binding
  • Protein Biosynthesis*
  • RNA, Messenger / genetics*
  • RNA, Messenger / immunology
  • Ribosomes / genetics
  • Ribosomes / immunology
  • Serine-Arginine Splicing Factors / genetics*
  • Serine-Arginine Splicing Factors / immunology
  • Signal Transduction
  • Transcription, Genetic


  • Lipopolysaccharides
  • RNA, Messenger
  • Srsf3 protein, mouse
  • Serine-Arginine Splicing Factors