PPM1A Regulates Antiviral Signaling by Antagonizing TBK1-Mediated STING Phosphorylation and Aggregation

PLoS Pathogens

Jianhang Jia¹  Zexing Li²  Liwei Sun²  Qinmiao Sun²  Yan Teng³  Xiao Yang³  Ge Liu⁴  Dahua Chen⁴  Jiahao Sha⁵  Xuejiang Guo⁵ 

[1] Markey Cancer Center, Department of Molecular and Cellular Biochemistry, The University of Kentucky College of Medicine, Lexington, Kentucky, United States of America;State Key Laboratory of Biomembrane and Membrane Biotechnology, Chinese Academy of Sciences, Chaoyang District, Beijing, China;State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, China;State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Chaoyang District, Beijing, China;State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China

关键词: Phosphorylation;    Immunoblotting;    Phosphatases;    Antiviral immune response;    Transfection;    Luciferase assay;    Plasmid construction;    Amino acid analysis;   

DOI  :  10.1371/journal.ppat.1004783

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY