PPM1A regulates antiviral signaling by antagonizing TBK1-mediated STING phosphorylation and aggregation

• Published in: PLoS pathogens 2015-03, Vol.11 (3), p.e1004783-e1004783
• Main Authors: Li, Zexing, Liu, Ge, Sun, Liwei, Teng, Yan, Guo, Xuejiang, Jia, Jianhang, Sha, Jiahao, Yang, Xiao, Chen, Dahua, Sun, Qinmiao
• Format: Article
• Language: English
• Subjects: Animals; Cellular signal transduction; Chlorocebus aethiops; Deoxyribonucleic acid; DNA; Endoplasmic reticulum; Experiments; HEK293 Cells; HeLa Cells; Host-parasite relationships; Humans; Identification and classification; Immune system; Infections; Inflammatory diseases; Kinases; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice; Mice, Knockout; Phosphatase; Phosphoprotein Phosphatases - genetics; Phosphoprotein Phosphatases - immunology; Phosphorylation; Phosphorylation - genetics; Phosphorylation - immunology; Protein Phosphatase 2C; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - immunology; Proteins; Regulation; Signal transduction; Signal Transduction - genetics; Signal Transduction - immunology; Vero Cells; Viral infections; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1004783

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.