Analysis of Drosophila STING Reveals an Evolutionarily Conserved Antimicrobial Function

Highlights

• Drosophila STING (dmSTING) associates with cyclic dinucleotides

• Flies knocked down or deleted for dmSTING are more susceptible to Listeria infection

• DmSTING functions in mammalian cells and activates NF-κB signaling

• DmSTING signals through the IMD pathway and stimulates Relish cleavage

Summary

The vertebrate protein STING, an intracellular sensor of cyclic dinucleotides, is critical to the innate immune response and the induction of type I interferon during pathogenic infection. Here, we show that a STING ortholog (dmSTING) exists in Drosophila, which, similar to vertebrate STING, associates with cyclic dinucleotides to initiate an innate immune response. Following infection with Listeria monocytogenes, dmSTING activates an innate immune response via activation of the NF-κB transcription factor Relish, part of the immune deficiency (IMD) pathway. DmSTING-mediated activation of the immune response reduces the levels of Listeria-induced lethality and bacterial load in the host. Of significance, dmSTING triggers an innate immune response in the absence of a known functional cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) ortholog in the fly. Together, our results demonstrate that STING is an evolutionarily conserved antimicrobial effector between flies and mammals, and it comprises a key component of host defense against pathogenic infection in Drosophila.