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

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.

Type I interferon-dependent CCL4 is induced by a cGAS/STING pathway that bypasses viral inhibition and protects infected tissue, independent of viral burden

“…However, production of both T1-IFN mRNA and protein, as well as protection against enhanced tissue pathology following VACV infection, was dependent upon cGAS, but not upon other PRR signaling pathways. This contrasts with other studies, which have demonstrated that cGAS is required to protect against VACV challenge, but which have stopped short of demonstrating a role for cGAS in T1-IFN production following VACV infection [18,37,38]. The lack of a link between cGAS and T1-IFN production following VACV infection in vivo likely stems from technical issues, and we developed a number of highly sensitive ex vivo approaches in order to be able to detect T1-IFN transcripts and protein from VACV-infected tissue.…”

“…Upstream of STING, cGAS has been implicated in the recognition of multiple virus infections, including VACV [18,37,38]. However, in addition to its well established role in induction of T1-IFN production, cGAS can also activate NF-B [39][40][41] and STAT6 [42,43], both of which can impact the anti-poxvirus immune response [44][45][46][47][48][49].…”

B Cell Receptor-Responsive miR-141 and viral miR-BART9 promote Epstein-Barr Virus Reactivation Through FOXO3 Inhibition

“…We specifically selected 3’UTRs of interest to either B cell or EBV biology. These included (i) FOXO3, encoding Forkhead box O3a, a member of the conserved forkhead box transcription factors (53), (ii) RANBP9, encoding an adaptor protein that interacts with Zta to augment reactivation (54), (iii) YY1, necessary for GC reactions (55) and binds multiple sites within Zp to repress Zta expression (21), (iv) ZCCHC3, encoding a co-sensor for cGAS (56), and (v) ZEB2, a transcriptional repressor of Zp (13, 22). Binding sites in these 3’UTRs represented a range of 6mer (nt 2-7) to 8mer (nt 2-9) seed matches for miR-141-3p and/or miR-BART9-3p (Fig.…”

“…Of note, we identified another common target of miR-141 and miR-BART9, ZCCHC3 (Fig. 5), that functions as a co-sensor for cGAS, activates the IFNbeta promoter, and contributes to innate immune responses directed against DNA virus infection in the cytosol (56). Overexpression of ZCCHC3 enhances herpes simplex virus 1 (HSV1) mediated activation of interferon response genes (56).…”

“…5), that functions as a co-sensor for cGAS, activates the IFNbeta promoter, and contributes to innate immune responses directed against DNA virus infection in the cytosol (56). Overexpression of ZCCHC3 enhances herpes simplex virus 1 (HSV1) mediated activation of interferon response genes (56). Thus, regulation of FOXO3 and ZCCHC3 levels by miR-141 and miR-BART9 may play an important role in modulating innate immune responses activated during EBV replication.…”