title: PPM1A silences cytosolic RNA sensing and antiviral defense through direct dephosphorylation of MAVS and TBK1.
abstract: Cytosolic RNA sensing is a prerequisite for initiation of innate immune response against RNA viral pathogens. Signaling through RIG-I (retinoic acid-inducible gene I)-like receptors (RLRs) to TBK1 (Tank-binding kinase 1)/IKKε (IκB kinase ε) kinases is transduced by mitochondria-associated MAVS (mitochondrial antiviral signaling protein). However, the precise mechanism of how MAVS-mediated TBK1/IKKε activation is strictly controlled still remains obscure. We reported that protein phosphatase magnesium-dependent 1A (PPM1A; also known as PP2Cα), depending on its catalytic ability, dampened the RLR-IRF3 (interferon regulatory factor 3) axis to silence cytosolic RNA sensing signaling. We demonstrated that PPM1A was an inherent partner of the TBK1/IKKε complex, targeted both MAVS and TBK1/IKKε for dephosphorylation, and thus disrupted MAVS-driven formation of signaling complex. Conversely, a high level of MAVS can dissociate the TBK1/PPM1A complex to override PPM1A-mediated inhibition. Loss of PPM1A through gene ablation in human embryonic kidney 293 cells and mouse primary macrophages enabled robustly enhanced antiviral responses. Consequently, Ppm1a(-/-) mice resisted to RNA virus attack, and transgenic zebrafish expressing PPM1A displayed profoundly increased RNA virus vulnerability. These findings identify PPM1A as the first known phosphatase of MAVS and elucidate the physiological function of PPM1A in antiviral immunity on whole animals.
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.
authors.forename: Weiwen
authors.initials: W
authors.lastname: Xiang
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Michael E. DeBakey Department of Surgery and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xia
authors.identifier: 0000-0002-2975-1532
authors.initials: X
authors.lastname: Lin
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.
authors.forename: Shiying
authors.initials: S
authors.lastname: Wu
authors.affiliation: Eye Center of the Second Affiliated Hospital School of Medicine, Institute of Translational Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yao
authors.identifier: 0000-0002-8814-090X
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Life Sciences Institute and 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 and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Michael E. DeBakey Department of Surgery and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.
authors.forename: Mu
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.
authors.forename: Zongping
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Eye Center of the Second Affiliated Hospital School of Medicine, Institute of Translational Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zou
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.; Michael E. DeBakey Department of Surgery and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.affiliation: Life Sciences Institute and 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: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified / Q000378:metabolism; D064113:CRISPR-Cas Systems / Q000235:genetics; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000378:metabolism / Q000821:virology; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D000071636:Protein Phosphatase 2C / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D029082:Sendai virus / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology; D018116:Vesiculovirus / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology; D015027:Zebrafish / Q000254:growth & development / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050838:Interferon Regulatory Factor-3; D034741:RNA, Small Interfering; D012313:RNA; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; C000607466:Ppm1a protein, mouse; D000071636:Protein Phosphatase 2C
keywords: MAVS; PPM1A; TBK1; antiviral host defense; cytosolic RNA sensing; phosphatase