HIV-1 蛋白的谷氨酰化通过劫持 STING 抑制免疫反应。

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

机构信息

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.

Biosafety Level 3 Laboratory, Fudan University, Shanghai 200032, China.

出版信息

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

DOI:10.1016/j.celrep.2023.112442

PMID:37099423

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, CoCl, 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.

摘要

环鸟苷酸-腺苷酸合酶（cGAS）识别人类免疫缺陷病毒 1 型（HIV-1）的 Y 形 cDNA，并通过 cGAS-干扰素基因刺激物（STING）-TBK1-IRF3 型 I 干扰素（IFN-I）信号级联反应启动抗病毒免疫反应。在这里，我们报告 HIV-1 p6 蛋白抑制 HIV-1 刺激的 IFN-I 表达并促进免疫逃逸。在机制上，残基 Glu6 上的谷氨酸化 p6 抑制 STING 和三肽基重复蛋白 32（TRIM32）或自分泌运动因子受体（AMFR）之间的相互作用。这随后抑制 STING 在 K337 处的 K27 和 K63 连接的多泛素化，从而抑制 STING 激活，而 Glu6 残基的突变部分逆转了抑制作用。然而，细胞溶质羧肽酶（CCPs）的激动剂 CoCl 抵消了 p6 在 Glu6 残基上的谷氨酸化并抑制了 HIV-1 的免疫逃逸。这些发现揭示了一种 HIV-1 蛋白介导免疫逃逸的机制，并提供了一种治疗 HIV-1 感染的治疗药物候选物。