PUBLICATION

Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation

Authors
Meng, F., Zhou, R., Wu, S., Zhang, Q., Jin, Q., Zhou, Y., Plouffe, S.W., Liu, S., Song, H., Xia, Z., Zhao, B., Ye, S., Feng, X.H., Guan, K.L., Zou, J., Xu, P.
ID
ZDB-PUB-170301-12
Date
2016
Source
Genes & Development   30: 1086-100 (Journal)
Registered Authors
Zou, Jian
Keywords
IRF3, Mst1, TBK1, host antiviral defense, phosphorylation
MeSH Terms
  • Animals
  • Cell Line
  • Cytosol/immunology*
  • Enzyme Activation/genetics
  • HEK293 Cells
  • Humans
  • Immunity, Innate/genetics*
  • Interferon Regulatory Factor-3/genetics
  • Interferon Regulatory Factor-3/metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Protein Binding
  • Protein Serine-Threonine Kinases/metabolism*
  • Rhabdoviridae Infections/enzymology*
  • Rhabdoviridae Infections/immunology*
  • Vesiculovirus/immunology
  • Zebrafish/immunology
PubMed
27125670 Full text @ Genes & Dev.
Abstract
Cytosolic RNA/DNA sensing elicits primary defense against viral pathogens. Interferon regulatory factor 3 (IRF3), a key signal mediator/transcriptional factor of the antiviral-sensing pathway, is indispensible for interferon production and antiviral defense. However, how the status of IRF3 activation is controlled remains elusive. Through a functional screen of the human kinome, we found that mammalian sterile 20-like kinase 1 (Mst1), but not Mst2, profoundly inhibited cytosolic nucleic acid sensing. Mst1 associated with IRF3 and directly phosphorylated IRF3 at Thr75 and Thr253. This Mst1-mediated phosphorylation abolished activated IRF3 homodimerization, its occupancy on chromatin, and subsequent IRF3-mediated transcriptional responses. In addition, Mst1 also impeded virus-induced activation of TANK-binding kinase 1 (TBK1), further attenuating IRF3 activation. As a result, Mst1 depletion or ablation enabled an enhanced antiviral response and defense in cells and mice. Therefore, the identification of Mst1 as a novel physiological negative regulator of IRF3 activation provides mechanistic insights into innate antiviral defense and potential antiviral prevention strategies.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping