| First Author | Meng F | Year | 2016 |
| Journal | Genes Dev | Volume | 30 |
| Issue | 9 | Pages | 1086-100 |
| PubMed ID | 27125670 | Mgi Jnum | J:232564 |
| Mgi Id | MGI:5779577 | Doi | 10.1101/gad.277533.116 |
| Citation | Meng F, et al. (2016) Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation. Genes Dev 30(9):1086-100 |
| abstractText | 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. |
