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A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
11:44

A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3

Published on: January 24, 2016

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Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation

Fansen Meng1, Ruyuan Zhou1, Shiying Wu1

  • 1Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China;

Genes & Development
|April 30, 2016
PubMed

Insights

Mammalian sterile 20-like kinase 1 (Mst1) inhibits cytosolic nucleic acid sensing by phosphorylating Interferon regulatory factor 3 (IRF3). Mst1 depletion enhances antiviral defense, revealing a novel regulator of innate immunity.

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • Cytosolic RNA/DNA sensing is crucial for innate antiviral defense.
  • Interferon regulatory factor 3 (IRF3) is a key transcription factor in antiviral signaling.
  • Mechanisms controlling IRF3 activation status are not fully understood.

Purpose of the Study:

  • To identify novel regulators of cytosolic nucleic acid sensing.
  • To elucidate the role of mammalian sterile 20-like kinase 1 (Mst1) in antiviral pathways.
  • To understand how Mst1 affects IRF3 activation and antiviral responses.

Main Methods:

  • Functional screening of the human kinome.
  • Co-immunoprecipitation assays to study protein interactions.
  • In vitro kinase assays and in vivo phosphorylation site mapping.
  • Analysis of IRF3 dimerization, chromatin occupancy, and transcriptional activity.
  • Assessment of antiviral responses in cell culture and mouse models.

Main Results:

  • Mammalian sterile 20-like kinase 1 (Mst1), but not Mst2, inhibits cytosolic nucleic acid sensing.
  • Mst1 directly phosphorylates IRF3 at Thr75 and Thr253, abolishing its homodimerization and chromatin binding.
  • Mst1 impedes TANK-binding kinase 1 (TBK1) activation, further reducing IRF3 activation.
  • Mst1 depletion or ablation enhances cellular and organismal antiviral defense.

Conclusions:

  • Mst1 acts as a novel physiological negative regulator of IRF3 activation.
  • Mst1-mediated phosphorylation of IRF3 is a key mechanism controlling innate antiviral immunity.
  • Targeting Mst1 could offer potential antiviral prevention strategies.
Keywords:
IRF3Mst1TBK1host antiviral defensephosphorylation

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