title: Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation.
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.
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China;
authors.forename: Fansen
authors.initials: F
authors.lastname: Meng
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China;
authors.forename: Ruyuan
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China;
authors.forename: Shiying
authors.initials: S
authors.lastname: Wu
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China;
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China;
authors.forename: Qiuheng
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Eye Center of the Second Affiliated Hospital School of Medicine, Zhejiang University, Hangzhou 310058, China; Institute of Translational Medicine, Zhejiang University, Hangzhou 310058, China;
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Steven W
authors.initials: SW
authors.lastname: Plouffe
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China;
authors.forename: Shengduo
authors.initials: S
authors.lastname: Liu
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China;
authors.forename: Hai
authors.initials: H
authors.lastname: Song
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China;
authors.forename: Zongping
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China;
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China;
authors.forename: Sheng
authors.initials: S
authors.lastname: Ye
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China; Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.affiliation: Department of Pharmacology, Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.affiliation: Eye Center of the Second Affiliated Hospital School of Medicine, Zhejiang University, Hangzhou 310058, China; Institute of Translational Medicine, Zhejiang University, Hangzhou 310058, China;
authors.forename: Jian
authors.initials: J
authors.lastname: Zou
authors.affiliation: Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China;
authors.forename: Pinglong
authors.identifier: 0000-0001-7726-5443
authors.initials: P
authors.lastname: Xu
mesh_terms: D000818:Animals; D002460:Cell Line; D003600:Cytosol / Q000276:immunology*; D004789:Enzyme Activation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D018353:Rhabdoviridae Infections / Q000201:enzymology* / Q000276:immunology*; D000090742:Serine-Threonine Kinase 3; D018116:Vesiculovirus / Q000276:immunology; D015027:Zebrafish / Q000276:immunology; D000099317:Hippo Kinases
chemical_list: D050838:Interferon Regulatory Factor-3; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; C494232:IRF3 protein, human; C498588:Tbk1 protein, mouse; C000614519:mammalian sterile 20-like kinase 1, human; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases
keywords: IRF3; Mst1; TBK1; host antiviral defense; phosphorylation