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

Publication date: Available online 26 January 2017
Source:Cell Host & Microbe
Author(s): Yu-Zhi Fu, Shan Su, Yi-Qun Gao, Pei-Pei Wang, Zhe-Fu Huang, Ming-Ming Hu, Wei-Wei Luo, Shu Li, Min-Hua Luo, Yan-Yi Wang, Hong-Bing Shu
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.

Graphical abstract

Teaser

Whether and how HCMV proteins target the host immune system for evasion is enigmatic. Fu et al. found that HCMV protein UL82 inhibits STING-mediated signaling by impairing its cellular trafficking and complex formation, leading to inhibition of innate antiviral response and immune evasion by HCMV.


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