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

Li, Yao; Slavik, Kailey M.; Toyoda, Hunter C.; Morehouse, Benjamin R.; Oliveira Mann, Carina C. de; Elek, Anamaria; Levy, Shani; Wang, Zhenwei; Mears, Kepler S.; Liu, Jingjing; Kashin, Dmitry; Guo, Ximing; Mass, Tali; Sebé-Pedrós, Arnau; Schwede, Frank; Kranzusch, Philip J.

doi:http://dx.doi.org/10.1016/j.cell.2023.05.038

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

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Li Y, Slavik KM, Toyoda HC, Morehouse BR, de Oliveira Mann CC, Elek A, Levy S, Wang Z, Mears KS, Liu J, Kashin D, Guo X, Mass T, Sebé-Pedrós A, Schwede F, Kranzusch PJ. cGLRs are a diverse family of pattern recognition receptors in innate immunity. Cell. 2023 Jul 20;186(15):3261-76.e20. DOI: 10.1016/j.cell.2023.05.038

Abstract

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.