cGLRs are a diverse family of pattern recognition receptors in innate immunity.

Cyclic GMP-AMP synthase (cGAS) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2′3′-cGAMP that activates STING-dependent downstream immunity. Here, we discover that cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in innate immunity. Building on recent analysis in Drosophila , we identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screening of 150 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of isomers of the nucleotide signals cGAMP, c-UMP-AMP, and c-di-AMP. Combining structural biology and in vivo analysis in coral and oyster animals, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity. [Display omitted] • Thousands of cGAS-like pattern recognition receptors (cGLRs) exist across animal taxa • Biochemical screening demonstrates that cGLRs sense dsDNA, dsRNA, and unknown ligands • cGLRs synthesize distinct nucleotide signals using both purine and pyrimidine bases • Animals encode multiple cGLRs and STINGs to form complex immune signaling networks The findings that a multitude of animals, from coral to mammals, encode cGAS-like signaling proteins, which produce an array of nucleotide second messenger signals, suggest that this family of pattern recognition receptors controls complex immune signaling networks that are broadly fundamental to animal innate immunity. [ABSTRACT FROM AUTHOR]