title: PPM1A regulates antiviral signaling by antagonizing TBK1-mediated STING phosphorylation and aggregation.
abstract: Stimulator of interferon genes (STING, also known as MITA and ERIS) is critical in protecting the host against DNA pathogen invasion. However, the molecular mechanism underlying the regulation of STING remains unclear. Here, we show that PPM1A negatively regulates antiviral signaling by targeting STING in its phosphatase activity-dependent manner, and in a line with this, PPM1A catalytically dephosphorylates STING and TBK1 in vitro. Importantly, we provide evidence that whereas TBK1 promotes STING aggregation in a phosphorylation-dependent manner, PPM1A antagonizes STING aggregation by dephosphorylating both STING and TBK1, emphasizing that phosphorylation is crucial for the efficient activation of STING. Our findings demonstrate a novel regulatory circuit in which STING and TBK1 reciprocally regulate each other to enable efficient antiviral signaling activation, and PPM1A dephosphorylates STING and TBK1, thereby balancing this antiviral signal transduction.
authors: State Key Laboratory of Biomembrane and Membrane Biotechnology, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
authors: Zexing
authors: Z
authors: Li
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
authors: Ge
authors: G
authors: Liu
authors: State Key Laboratory of Biomembrane and Membrane Biotechnology, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
authors: Liwei
authors: L
authors: Sun
authors: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, China.
authors: Yan
authors: Y
authors: Teng
authors: State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
authors: Xuejiang
authors: X
authors: Guo
authors: Markey Cancer Center, Department of Molecular and Cellular Biochemistry, The University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
authors: Jianhang
authors: J
authors: Jia
authors: State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China.
authors: Jiahao
authors: J
authors: Sha
authors: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, China.
authors: Xiao
authors: X
authors: Yang
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
authors: Dahua
authors: D
authors: Chen
authors: State Key Laboratory of Biomembrane and Membrane Biotechnology, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
authors: Qinmiao
authors: Q
authors: Sun
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014709:Vero Cells; D000099197:STING Protein
chemical_list: D008565:Membrane Proteins; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse; C498588:Tbk1 protein, mouse; C403191:TBK1 protein, human; C000607456:PPM1A protein, human; C000607466:Ppm1a protein, mouse