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.
Highlights
Microbial nucleic acids are major PAMPs that are sensed by cellular PRRs after microbial infection
Reporter assays indicated that overexpression of ZCCHC3 activated the IFN-β promoter by itself and potentiated herpes simplex virus 1 (HSV-1)-induced activation of the IFN-β promoter in a dose-dependent manner in HEK293 cells (Fig. 1a). qPCR experiments indicated that overexpression of ZCCHC3 potentiated HSV-1-induced transcription of IFNB1, ISG56 and CXCL10 genes in primary human foreskin fibroblasts (HFFs) (Fig. 1b)
It has been well established that Cyclic GMP-AMP synthase (cGAS) is a ubiquitous sensor for cytosolic dsDNA, which plays an essential role in innate immune response to microbial and dis-located self DNA15,23
Summary
Microbial nucleic acids are major PAMPs that are sensed by cellular PRRs after microbial infection. It has been shown that several DNA sensors including Sox[26], TLR97, AIM28, DAI9, RNA polymerase III10,11, IFI1612, DDX4113, and LSm14A14 can detect cytosolic or microbial DNA in distinct cells or mouse models. These proteins are not universally required for cytosolic DNA sensing in distinct cell types or in vivo[5]. Genetic studies have demonstrated that cGAS plays crucial roles in innate immune responses to cytosolic DNA and various DNA viruses[23]. We identified the CCHC-type zinc-finger (ZF) protein ZCCHC3 as a co-sensor of cGAS in innate immune response to cytosolic dsDNA and DNA virus. Our findings suggest that ZCCHC3 acts as a co-sensor of cGAS for recognition of dsDNA and plays an essential role in innate immune response to DNA virus
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