2′3′-cGAMP triggers a STING- and NF-κB–dependent broad antiviral response in Drosophila.

STINGing viruses without interferon: The adaptor protein STING induces the production of antiviral interferons in response to the cyclic dinucleotide 2′3′-cGAMP generated as a "danger" signal during viral infection of mammalian cells. Drosophila have a STING ortholog but do not produce interferons. Cai et al. found that exogenously administered 2′3′-cGAMP protected Drosophila against multiple DNA and RNA viruses in a manner dependent on STING and the transcription factor Relish, an ortholog of NF-κB. This antiviral immunity did not involve autophagy, a cellular process in which STING plays an evolutionarily conserved role and that can restrict viral replication, or RNA interference, an antiviral response in Drosophila. These results suggest that 2′3′-cGAMP as a viral danger signal is evolutionarily older than previously suspected and that STING was incorporated into the interferon response during vertebrate evolution. We previously reported that an ortholog of STING regulates infection by picorna-like viruses in Drosophila. In mammals, STING is activated by the cyclic dinucleotide 2′3′-cGAMP produced by cGAS, which acts as a receptor for cytosolic DNA. Here, we showed that injection of flies with 2′3′-cGAMP induced the expression of dSTING-regulated genes. Coinjection of 2′3′-cGAMP with a panel of RNA or DNA viruses resulted in substantially reduced viral replication. This 2′3′-cGAMP–mediated protection was still observed in flies with mutations in Atg7 and AGO2, genes that encode key components of the autophagy and small interfering RNA pathways, respectively. By contrast, this protection was abrogated in flies with mutations in the gene encoding the NF-κB transcription factor Relish. Transcriptomic analysis of 2′3′-cGAMP–injected flies revealed a complex response pattern in which genes were rapidly induced, induced after a delay, or induced in a sustained manner. Our results reveal that dSTING regulates an NF-κB–dependent antiviral program that predates the emergence of interferons in vertebrates. [ABSTRACT FROM AUTHOR]