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bioRxiv · 10.1101/2023.02.22.529553

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

Li, Y.·Slavik, K. M.·Morehouse, B. R.·Mann, C. C. d. O.·Mears, K.·Liu, J.·Kashin, D.·Schwede, F.·Kranzusch, P. J.
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Abstract

cGAS (cyclic GMP-AMP synthase) 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 the protein STING and downstream immunity. Here we discover cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in animal innate immunity. Building on recent analysis in Drosophila, we use a bioinformatic approach to identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screen of 140 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of alternative nucleotide signals including isomers of cGAMP and cUMP-AMP. Using structural biology, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Together our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.

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Li, Y., Slavik, K. M., Morehouse, B. R., Mann, C. C. d. O., Mears, K., Liu, J., Kashin, D., Schwede, F., Kranzusch, P. J.. 2023-02-22. cGLRs are a diverse family of pattern recognition receptors in animal innate immunity. https://doi.org/10.1101/2023.02.22.529553

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