title: The ER-associated protein ZDHHC1 is a positive regulator of DNA virus-triggered, MITA/STING-dependent innate immune signaling.
abstract: Viral DNA sensing within the cytosol of infected cells activates type I interferon (IFN) expression. MITA/STING plays an essential role in this pathway by acting as both a sensor for the second messenger cGAMP and as an adaptor for downstream signaling components. In an expression screen for proteins that can activate the IFNB1 promoter, we identified the ER-associated protein ZDHHC1 as a positive regulator of virus-triggered, MITA/STING-dependent immune signaling. Zdhhc1(-/-) cells failed to effectively produce IFNs and other cytokines in response to infection with DNA but not RNA viruses. Zdhhc1(-/-) mice infected with the neurotropic DNA virus HSV-1 exhibited lower cytokine levels and higher virus titers in the brain, resulting in higher lethality. ZDHHC1 constitutively associated with MITA/STING and mediates dimerization/aggregation of MITA/STING and recruitment of the downstream signaling components TBK1 and IRF3. These findings support a role for ZDHHC1 in mediating MITA/STING-dependent innate immune response against DNA viruses.
authors.affiliation: Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430072, China.
authors.forename: Suyun
authors.initials: S
authors.lastname: Wang
authors.affiliation: Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430072, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ran
authors.affiliation: Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Ye
authors.affiliation: Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Xiaozhe
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhong
authors.affiliation: Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address: shuh@whu.edu.cn.
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shu
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430072, China. Electronic address: wangyy@wh.iov.cn.
authors.forename: Yan-Yi
authors.initials: YY
authors.lastname: Wang
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000473:pathology / Q000821:virology; D002460:Cell Line; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D020803:Encephalitis, Herpes Simplex / Q000276:immunology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000096:biosynthesis*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D016019:Survival Analysis; D019562:Viral Load; D000099197:STING Protein
chemical_list: D000217:Acyltransferases; D016207:Cytokines; D016899:Interferon-beta; D008565:Membrane Proteins; C532857:STING1 protein, human; D000099197:STING Protein; C486179:ZDHHC1 protein, human