Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication

Abstract

<p id="P3">Herpes simplex virus-1 (HSV-1) establishes infections in humans and mice but some non-human primates exhibit resistance via unknown mechanisms. Innate immune recognition pathways are highly conserved but are pivotal in determining susceptibility to DNA virus infections. We report that variation of a single amino acid residue in the innate immune sensor cGAS determines species-specific inactivation by HSV-1. The HSV-1 UL37 tegument protein deamidates human and mouse cGAS. Deamidation impairs the ability of cGAS to catalyze cGAMP synthesis, which activates innate immunity. HSV-1 with deamidase-deficient UL37 promotes robust antiviral responses and is attenuated in mice, in a cGAS- and STING-dependent manner. Mutational analyses identified a single asparagine in human and mouse cGAS that is not conserved in many non-human primates. This residue underpins UL37-mediated cGAS deamidation and species permissiveness of HSV-1. Thus, HSV-1 mediates cGAS deamidation for immune evasion and exploits species sequence variation to disarm host defenses. </p><p id="P4"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/8ceaa965-c28b-4a73-bb48-89c002b1c5f5/PubMedCentral/image/nihms1500530u1.jpg"/> </div> </p><p id="P5">Natural sequence variations in immune factors may enable viral pathogens to evade or dismantle host defenses. Zhang et al report herpes simplex virus-1 exploits species-specific variation of a single amino acid residue in cGAS for deamidation, thereby inactivating innate defense in susceptible hosts. </p>