Abstract:

<p>Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that produces the second messenger 2&#39;3&#39;-cGAMP and controls activation of innate immunity in mammalian cells. Animal genomes typically encode multiple proteins with predicted homology to cGAS, but the function of these uncharacterized enzymes is unknown. Here we show that cGAS-like receptors (cGLRs) are innate immune sensors capable of recognizing divergent molecular patterns and catalyzing synthesis of distinct nucleotide second messenger signals. Crystal structures of human and insect cGLRs reveal a nucleotidyltransferase signaling core shared with cGAS and a diversified primary ligand-binding surface modified with significant insertions and deletions. We demonstrate that cGLR surface remodeling enables altered ligand specificity and use a forward biochemical screen to identify cGLR1 as a double-stranded RNA sensor in the model organism Drosophila melanogaster. Surprisingly, RNA recognition activates Drosophila cGLR1 to synthesize the novel product cG[3&#39;-5&#39;]pA[2&#39;-5&#39;]p (3&#39;2&#39;-cGAMP). A crystal structure of Drosophila Stimulator of Interferon Genes (STING) in complex with 3&#39;2&#39;-cGAMP explains selective isomer recognition and we demonstrate that 3&#39;2&#39;-cGAMP induces an enhanced antiviral state in vivo that protects from viral infection. Similar to radiation of Toll-like receptors in pathogen immunity, our results establish cGLRs as a diverse family of metazoan pattern recognition receptors.</p>