2. Academic Validation
  3. ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response

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

  • Nat Commun. 2018 Aug 22;9(1):3349. doi: 10.1038/s41467-018-05559-w.
Huan Lian 1,  Jin Wei 1,  Ru Zang 1,  Wen Ye 1,  Qing Yang 1,  Xia-Nan Zhang 1 2,  Yun-Da Chen 1 2,  Yu-Zhi Fu 3,  Ming-Ming Hu 1,  Cao-Qi Lei 1 2,  Wei-Wei Luo 3,  Shu Li 4,  Hong-Bing Shu 5 6
Affiliations

Affiliations

  • 1 Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.
  • 2 College of Life Sciences Wuhan University, 430072, Wuhan, China.
  • 3 Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China.
  • 4 Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China. shuli@whu.edu.cn.
  • 5 Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China. shuh@whu.edu.cn.
  • 6 College of Life Sciences Wuhan University, 430072, Wuhan, China. shuh@whu.edu.cn.
PMID: 30135424 DOI: 10.1038/s41467-018-05559-w
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.

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