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
  • 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. [email protected].
  • 5. Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China. [email protected].
  • 6. College of Life Sciences Wuhan University, 430072, Wuhan, China. [email protected].
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.