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

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 in-hibits the interaction between STING and tripartite motif protein 32 (TRIM32) or autocrine motility factor recep-tor (AMFR). This subsequently suppresses the K27-and K63-linked polyubiquitination of STING at K337, there-fore 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.

Automated summary

Cyclic GMP-AMP synthase (cGAS) recognizes Y-form cDNA of HIV-1 and initiates antiviral immune response, but the p6 protein of HIV-1 suppresses IFN-I expression and promotes immune evasion. Glutamylated p6 inhibits STING interaction with TRIM32 or AMFR, suppressing STING activation by inhibiting K27 and K63 polyubiquitination at K337. CoCl2, a CCP agonist, counteracts p6 glutamylation and inhibits HIV-1 immune evasion.