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

Human Cytomegalovirus Tegument Protein UL82 Inhibits STING-Mediated Signaling to Evade AntiviralImmunity.

Fu YZ¹, Su S², Gao YQ¹, Wang PP², Huang ZF³, Hu MM², Luo WW², Li S¹, Luo MH³, Wang YY³, Shu HB⁴.

Author information

·         ¹State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China 430072.

·         ²Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Wuhan, China 430071.

·         ³Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China 430071.

·         ⁴State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China 430072; Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Wuhan, China 430071. Electronic address: shuh@whu.edu.cn.

Abstract

Recognition of human cytomegalovirus (HCMV) DNA by the cytosolic sensor cGAS initiates STING-dependent innate antiviralresponses. 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 downstreamantiviral 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