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IRAK2 directs stimulus-dependent nuclear export of inflammatory mRNAs

Hao Zhou1, Katarzyna Bulek1,2, Xiao Li3

  • 1Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States.

Elife
|October 10, 2017
PubMed

Insights

Lipopolysaccharide (LPS) activates Interleukin-1 Receptor-Associated Kinase 2 (IRAK2) in the nucleus. This promotes the export of inflammatory messenger RNAs (mRNAs) for translation, controlling gene expression.

Area of Science:

  • Immunology
  • Molecular Biology
  • Post-transcriptional Regulation

Background:

  • Post-transcriptional regulation, including mRNA metabolism, controls inflammatory gene expression.
  • The precise mechanisms of stimulus- and transcript-dependent nuclear export in inflammation are not fully understood.

Purpose of the Study:

  • To elucidate a novel pathway involving IRAK2 in the nuclear export of inflammatory mRNAs.
  • To investigate the role of IRAK2 kinase activity and its interaction with other proteins in regulating mRNA export.

Main Methods:

  • Murine macrophages were treated with LPS to activate the TLR4 pathway.
  • Nuclear localization and translocation of IRAK2 were assessed.
  • IRAK2 sumoylation and its dependence on kinase activity were analyzed.
  • RNA immunoprecipitation (RIP) and array analysis were used to identify IRAK2-dependent mRNAs and binding motifs.
  • Phosphorylation of SRSF1 by nuclear IRAK2 and its effect on RNA binding adaptors were investigated.

Main Results:

  • LPS/TLR4 engagement induces nuclear localization of IRAK2 in macrophages.
  • IRAK2 kinase activity is essential for its sumoylation by RanBP2 and subsequent nuclear translocation.
  • mRNAs containing SRSF1-binding motifs are preferentially exported via an IRAK2-dependent pathway.
  • Nuclear IRAK2 phosphorylates SRSF1, reducing its mRNA binding and facilitating ALYREF and Nxf1 loading for export.
  • This pathway selectively exports specific inflammation-related mRNAs for cytoplasmic translation.

Conclusions:

  • LPS activates a nuclear function of IRAK2 that is critical for inflammatory gene expression.
  • IRAK2 acts as a key regulator of mRNA nuclear export by modulating the RNA-binding protein complex.
  • This pathway provides new insights into the post-transcriptional control of inflammation.
Keywords:
RNA exportcell biologyimmunologyinflammationmousenuclear translocationsumoylationtoll-like receptor

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