Human Cytomegalovirus Protein UL94 Targets MITA to Evade Antiviral Immune Response.

Cyclic GMP-AMP synthase (cGAS) senses double-stranded DNA and synthesizes the second messenger cyclic GMP-AMP (cGAMP) which binds to mediator of IRF3 activation (MITA) and initiates MITA-mediated signaling, leading to induction of type I interferons (IFNs) and other antiviral effectors. Human cytomegalovirus (HCMV), a widespread and opportunistic pathogen, antagonizes host antiviral immune response to establish latent infection. Here we identified HCMV tegument protein UL94 as an inhibitor of cGAS-MITA-mediated antiviral response. Ectopic expression of UL94 impaired cytosolic dsDNA- and DNA virus-triggered induction of type I IFNs and enhanced viral replication. Conversely, UL94-deficiency potentiated HCMV-induced transcription of type I IFNs and downstream antiviral effectors and impaired viral replication. UL94 interacted with MITA, disrupted the dimerization and translocation of MITA, and impaired the recruitment of TBK1 to the MITA signalosome. These results suggest that UL94 plays an important role in the immune evasion of HCMV.Importance Human cytomegalovirus (HCMV), a large dsDNA virus, encodes more than 200 viral proteins. HCMV infection causes irreversible abnormalities of central nervous system in newborns and severe syndromes in organ transplantation patients or AIDS patients. It has been demonstrated that HCMV has evolved multiple immune evasion strategies to establish latent infection. Previous studies pay more attention to the mechanism by which HCMV evades immune response in the early phase of infection. In this study, we identified UL94 as a negative regulator of innate immune response, which functions in the late phase of HCMV infection.