Species-specific Deamidation of cGAS Facilitates Herpes Simplex Virus Lytic Replication

Abstract

Host innate immune pathways are highly conserved in higher eukaryotes. Significance of the species-specific variation of innate immune components has not been explored with regard to DNA viruses. Here, we report the identification of a single site variation that defines the resistance of the cytosolic DNA sensor cGAS of nonhuman primates (NHPs) to deamidation mediated by human herpes simplex virus 1 (HSV-1). HSV-1 UL37, but not the deamidase-deficient UL37C819S mutant, deamidated human and mouse cGAS in vitro and in transfected cells. Biochemical analysis identified four sites of deamidation distributed throughout the Mab21 domain of cGAS. While deamidation did not significantly impair the DNA-binding and self-dimerizing activities of cGAS, deamidated cGAS failed to catalyze the synthesis of cGAMP that activates innate immune signaling to restrict DNA virus replication. Moreover, recombinant HSV-1 carrying the deamidase-inactivating C819S point mutation more robustly induced antiviral cytokine production and was highly attenuated in replication and pathogenesis in mice compared to HSV-1 wild-type, in a cGAS- and STING-dependent manner. Sequence comparison and mutational analyses defined a single asparagine within the activation loop of cGAS of human and mouse, but not most NHP cGASs, which underpins cGAS deamidation by UL37 and species permissiveness of HSV-1. This work uncovers a key role of protein deamidation in immune evasion whereby a human pathogen has evolved to exploit species sequence variation to disarm host immune defense.