The ER-Associated Protein ZDHHC1 Is a Positive Regulator of DNA Virus-Triggered, MITA/STING-Dependent Innate Immune Signaling

被引:134
作者
Zhou, Qian [1 ]
Lin, Heng [1 ]
Wang, Suyun [2 ]
Wang, Shuai [1 ]
Ran, Yong [2 ]
Liu, Ying [1 ]
Ye, Wen [1 ]
Xiong, Xiaozhe [1 ]
Zhong, Bo [1 ]
Shu, Hong-Bing [1 ]
Wang, Yan-Yi [2 ]
机构
[1] Wuhan Univ, Med Res Inst, Coll Life Sci, Wuhan 430072, Peoples R China
[2] Chinese Acad Sci, Wuhan Inst Virol, State Key Lab Virol, Wuhan 430072, Peoples R China
基金
中国国家自然科学基金;
关键词
CYCLIC GMP-AMP; CYTOSOLIC DNA; ENDOPLASMIC-RETICULUM; INTRACELLULAR DNA; ANTIVIRAL RESPONSE; DENDRITIC CELLS; NUCLEIC-ACIDS; RECOGNITION; PATHWAY; ADAPTER;
D O I
10.1016/j.chom.2014.09.006
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
引用
收藏
页码:450 / 461
页数:12
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