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

J Virol. 2020 Jun 1;94(12):e00022-20. doi: 10.1128/JVI.00022-20. Print 2020 Jun 1.

Abstract

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 the host antiviral immune response to establish latent infection. Here, we identified HCMV tegument protein UL94 as an inhibitor of the cGAS-MITA-mediated antiviral response. Ectopic expression of UL94 impaired cytosolic double-stranded DNA (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 signalsome. These results suggest that UL94 plays an important role in the immune evasion of HCMV.IMPORTANCE Human cytomegalovirus (HCMV), a large double-stranded DNA (dsDNA) virus, encodes more than 200 viral proteins. HCMV infection causes irreversible abnormalities of the 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 the innate immune response, which functions in the late phase of HCMV infection.

Keywords: HCMV; MITA/STING; UL94; antiviral innate immunity; immune evasion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Capsid Proteins / genetics
  • Capsid Proteins / immunology*
  • Cell Nucleus / immunology
  • Cell Nucleus / virology
  • Cyclic GMP / immunology
  • Cyclic GMP / metabolism
  • Cytomegalovirus / genetics
  • Cytomegalovirus / growth & development
  • Cytomegalovirus / immunology*
  • Cytosol / immunology
  • Cytosol / virology
  • DNA / immunology
  • DNA / metabolism
  • Exome Sequencing
  • Fibroblasts / immunology
  • Fibroblasts / virology
  • Gene Expression Regulation
  • Genome, Viral*
  • HEK293 Cells
  • Humans
  • Immune Evasion*
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / immunology
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Primary Cell Culture
  • Protein Binding
  • Protein Multimerization
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / immunology*
  • Protein Transport
  • RNA, Small Interfering / genetics*
  • RNA, Small Interfering / immunology
  • Signal Transduction

Substances

  • Capsid Proteins
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Membrane Proteins
  • RNA, Small Interfering
  • STING1 protein, human
  • UL94 protein, Human cytomegalovirus
  • DNA
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human
  • Cyclic GMP