Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation.
Fansen MengRuyuan ZhouShiying WuQian ZhangQiuheng JinYao ZhouSteven W PlouffeShengduo LiuHai SongZongping XiaBin ZhaoSheng YeXin-Hua FengKun-Liang GuanJian ZouPing-Long XuPublished in: Genes & development (2016)
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.
Keyphrases
- dendritic cells
- nucleic acid
- transcription factor
- immune response
- gene expression
- endothelial cells
- induced apoptosis
- dna damage
- type diabetes
- genome wide
- metabolic syndrome
- risk assessment
- skeletal muscle
- gram negative
- cell proliferation
- cell death
- high glucose
- antimicrobial resistance
- atrial fibrillation
- binding protein
- dna binding
- radiofrequency ablation