ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response

Huan Lian, Jin Wei, Ru Zang, Wen Ye, Qing Yang, Xia-Nan Zhang, Yun-Da Chen, Yu-Zhi Fu, Ming-Ming Hu, Cao-Qi Lei, Wei-Wei Luo, Shu Li () and Hong-Bing Shu ()
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Huan Lian: Wuhan University
Jin Wei: Wuhan University
Ru Zang: Wuhan University
Wen Ye: Wuhan University
Qing Yang: Wuhan University
Xia-Nan Zhang: Wuhan University
Yun-Da Chen: Wuhan University
Yu-Zhi Fu: Chinese Academy of Sciences
Ming-Ming Hu: Wuhan University
Cao-Qi Lei: Wuhan University
Wei-Wei Luo: Chinese Academy of Sciences
Shu Li: Wuhan University
Hong-Bing Shu: Wuhan University

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Cyclic GMP-AMP synthase (cGAS) senses double-strand (ds) DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the adaptor MITA/STING to initiate innate antiviral response. How cGAS activity is regulated remains enigmatic. Here, we identify ZCCHC3, a CCHC-type zinc-finger protein, as a positive regulator of cytosolic dsDNA- and DNA virus-triggered signaling. We show that ZCCHC3-deficiency inhibits dsDNA- and DNA virus-triggered induction of downstream effector genes, and that ZCCHC3-deficient mice are more susceptible to lethal herpes simplex virus type 1 or vaccinia virus infection. ZCCHC3 directly binds to dsDNA, enhances the binding of cGAS to dsDNA, and is important for cGAS activation following viral infection. Our results suggest that ZCCHC3 is a co-sensor for recognition of dsDNA by cGAS, which is important for efficient innate immune response to cytosolic dsDNA and DNA virus.

Date: 2018
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DOI: 10.1038/s41467-018-05559-w

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