Function And Mechanism Study Of Mst1 In Antiviral Host Defense

Cytosolic RNA/DNA sensing constitutes one of the key components of pattern recognition receptor(PRR)signaling,and elicits primary defense against viral pathogens which have invaded and infested within host cell.RIG-I-like receptors are responsible for recognition of RNA viruses,while cGAS,a recently identified cytosolic DNA sensor,is important in detecting viral DNA in cytosol.The sensing of exogenous RNA/DNA by cytosolic receptors leads to the activation of NF-κB pathway and Tank-binding kinase 1(TBK1),which subsequently phosphorylates and thus activates IRF3,the key signal mediator and transcriptional factor of antiviral defense.Type I/III Interferons,which are downstream targets of IRF3,initiate an antiviral response for production of hundreds of interferon-stimulated genes(ISGs),to control and clear virus infection.Despite the importance,still little is known about how the status of IRF3 activation is controlled.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.