Herpes simplex virus protein UL56 inhibits cGAS-Mediated DNA sensing to evade antiviral immunity

After herpes simplex virus type 1 (HSV-1) infection, the cytosolic sensor cyclic GMP-AMP synthase (cGAS) recognizes DNA and catalyzes synthesis of the second messenger 2'3'-cGAMP. cGAMP binds to the ER-localized adaptor protein MITA (also known as STING) to activate downstream antiviral responses. Conversely, HSV-1-encoded proteins evade antiviral immune responses via a wide variety of delicate mechanisms, promoting viral replication and pathogenesis. Here, we identified HSV-1 envelop protein UL56 as a negative regulator of cGAS-mediated innate immune responses. Overexpression of UL56 inhibited double-stranded DNA-triggered antiviral responses, whereas UL56-deficiency increased HSV-1-triggered induction of downstream antiviral genes. UL56-deficiency inhibited HSV-1 replication in wild-type but not MITA-deficient cells. UL56-deficient HSV-1 showed reduced replication in the brain of infected mice and was less lethal to infected mice. Mechanistically, UL56 interacted with cGAS and inhibited its DNA binding and enzymatic activity. Furthermore, we found that UL56 homologous proteins from different herpesviruses had similar roles in antagonizing cGAS-mediated innate immune responses. Our findings suggest that UL56 is a component of HSV-1 evasion of host innate immune responses by antagonizing the DNA sensor cGAS, which contributes to our understanding of the comprehensive mechanisms of immune evasion by herpesviruses.