ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response.
Author:  Date:2018-08-22  Clicks:
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.

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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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