Abstract
In mammals, the enzyme cGAS senses the presence of cytosolic DNA and synthesizes the cyclic dinucleotide (CDN) 2'3'-cGAMP, which triggers STING-dependent immunity. In Drosophila melanogaster, two cGAS-like receptors (cGLRs) produce 3'2'-cGAMP and 2'3'-cGAMP to activate STING. We explored CDN-mediated immunity in 14 Drosophila species covering 50 million years of evolution and found that 2'3'-cGAMP and 3'2'-cGAMP failed to control infection by Drosophila C virus in D.serrata and two other species. We discovered diverse CDNs produced in a cGLR-dependent manner in response to viral infection in D.melanogaster, including 2'3'-c-di-GMP. This CDN was a more potent STING agonist than cGAMP in D.melanogaster and it also activated a strong antiviral transcriptional response in D.serrata. Our results shed light on the evolution of cGLRs in flies and provide a basis for understanding the function and regulation of this emerging family of pattern recognition receptors in animal innate immunity.
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