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.
Lian H
1,
Wei J
1,
Zang R
1,
Ye W
1,
Yang Q
1,
Zhang XN
1,
2,
Chen YD
1,
2,
Fu YZ
3,
Hu MM
1,
Lei CQ
1,
2,
Luo WW
3,
Li S
4,
Shu HB
5,
6.
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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