Human Cytomegalovirus Tegument Protein UL82 Inhibits STING-Mediated Signaling to Evade Antiviral Immunity

Cell Host Microbe. 2017 Feb 8;21(2):231-243. doi: 10.1016/j.chom.2017.01.001. Epub 2017 Jan 26.

Abstract

Recognition of human cytomegalovirus (HCMV) DNA by the cytosolic sensor cGAS initiates STING-dependent innate antiviral responses. HCMV can antagonize host immune responses to promote latency infection. However, it is unknown whether and how HCMV targets the cGAS-STING axis for immune evasion. Here we identified the HCMV tegument protein UL82 as a negative regulator of STING-dependent antiviral responses. UL82 interacted with STING and impaired STING-mediated signaling via two mechanisms. UL82 inhibited the translocation of STING from the ER to perinuclear microsomes by disrupting the STING-iRhom2-TRAPβ translocation complex. UL82 also impaired the recruitment of TBK1 and IRF3 to the STING complex. The levels of downstream antiviral genes induced by UL82-deficient HCMV were higher than those induced by wild-type HCMV. Conversely, wild-type HCMV replicated more efficiently than the UL82-deficient mutant. These findings reveal an important mechanism of immune evasion by HCMV.

Keywords: HCMV; MITA; STING; UL82; cGAS; iRhom2; immune evasion; innate immunity; virus.

MeSH terms

  • Cytomegalovirus / genetics*
  • Cytomegalovirus / physiology
  • Gene Expression Regulation, Viral*
  • Humans
  • Immune Evasion*
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Protein Transport
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*
  • Virus Replication

Substances

  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Membrane Proteins
  • STING1 protein, human
  • Viral Proteins
  • cytomegalovirus phosphoprotein 71kDa
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human