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Nat Commun. 2018 Aug 22;9(1):3349. doi: 10.1038/s41467-018-05559-w.

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

Author information

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.

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.

PMID:
30135424
PMCID:
PMC6105683
DOI:
10.1038/s41467-018-05559-w
[Indexed for MEDLINE]
Free PMC Article

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