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

doi:10.1016/j.celrep.2023.112442

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

Cell Rep. 2023 May 30;42(5):112442. doi: 10.1016/j.celrep.2023.112442. Epub 2023 Apr 25.

Authors

Gui Qian¹, Yihua Zhang¹, Yinan Liu¹, Manman Li¹, Bowen Xin¹, Wenyi Jiang¹, Wendong Han², Yu Wang³, Xian Tang⁴, Liuyan Li¹, Lingyan Zhu¹, Tao Sun¹, Bo Yan¹, Yongtang Zheng⁵, Jianqing Xu⁶, Baoxue Ge⁷, Zheng Zhang⁴, Dapeng Yan⁸

Affiliations

¹ 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.
² Biosafety Level 3 Laboratory, Fudan University, Shanghai 200032, China.
³ National Engineering Research Centre of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Army Medical University, Chongqing 400038, China.
⁴ 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.
⁵ 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.
⁶ Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital & Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
⁷ Shanghai TB Key Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
⁸ 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. Electronic address: dapengyan@fudan.edu.cn.

PMID: 37099423
DOI: 10.1016/j.celrep.2023.112442

Abstract

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.

Keywords: CP: Immunology; HIV-1; STING; glutamylation; immune evasion; p6.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

HIV-1* / metabolism
Humans
Immunity, Innate / genetics
Membrane Proteins / metabolism
Nucleotidyltransferases / metabolism
Signal Transduction

Substances

Membrane Proteins
Nucleotidyltransferases