Glutamylation of an HIV-1 protein inhibits the immune response by hijacking STING

Gui Qian; Yihua Zhang; Yinan Liu; Manman Li; Bowen Xin; Wenyi Jiang; Wendong Han; Yu Wang; Xian Tang; Liuyan Li; Lingyan Zhu; Tao Sun; Bo Yan; Yongtang Zheng; Jianqing Xu; Baoxue Ge; Zheng Zhang; Dapeng Yan

Cell Reports (May 2023)

Glutamylation of an HIV-1 protein inhibits the immune response by hijacking STING

Gui Qian,
Yihua Zhang,
Yinan Liu,
Manman Li,
Bowen Xin,
Wenyi Jiang,
Wendong Han,
Yu Wang,
Xian Tang,
Liuyan Li,
Lingyan Zhu,
Tao Sun,
Bo Yan,
Yongtang Zheng,
Jianqing Xu,
Baoxue Ge,
Zheng Zhang,
Dapeng Yan

Affiliations

Gui Qian: Department of Immunology, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China
Yihua Zhang: Department of Immunology, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China
Yinan Liu: Department of Immunology, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China
Manman Li: Department of Immunology, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China
Bowen Xin: Department of Immunology, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China
Wenyi Jiang: Department of Immunology, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China
Wendong Han: Biosafety Level 3 Laboratory, Fudan University, Shanghai 200032, China
Yu Wang: National Engineering Research Centre of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Army Medical University, Chongqing 400038, China
Xian Tang: Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong Province 518112, China
Liuyan Li: Department of Immunology, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China
Lingyan Zhu: Department of Immunology, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China
Tao Sun: Department of Immunology, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China
Bo Yan: Department of Immunology, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China
Yongtang Zheng: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
Jianqing Xu: Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital & Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
Baoxue Ge: Shanghai TB Key Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
Zheng Zhang: Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong Province 518112, China
Dapeng Yan: Department of Immunology, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China; Corresponding author

Journal volume & issue: Vol. 42, no. 5
p. 112442

Abstract

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Summary: Cyclic GMP-AMP synthase (cGAS) recognizes Y-form cDNA of human immunodeficiency virus type 1 (HIV-1) and initiates antiviral immune response through cGAS-stimulator of interferon genes (STING)-TBK1-IRF3-type I interferon (IFN-I) signalingcascade. Here, we report that the HIV-1 p6 protein suppresses HIV-1-stimulated expression of IFN-I and promotes immune evasion. Mechanistically, the glutamylated p6 at residue Glu6 inhibits the interaction between STING and tripartite motif protein 32 (TRIM32) or autocrine motility factor receptor (AMFR). This subsequently suppresses the K27- and K63-linked polyubiquitination of STING at K337, therefore inhibiting STING activation, whereas mutation of the Glu6 residue partially reverses the inhibitory effect. However, CoCl2, an agonist of cytosolic carboxypeptidases (CCPs), counteracts the glutamylation of p6 at the Glu6 residue and inhibits HIV-1 immune evasion. These findings reveal a mechanism through which an HIV-1 protein mediates immune evasion and provides a therapeutic drug candidate to treat HIV-1 infection.

CP: Immunology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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