Li, Yao, Slavik, Kailey, Morehouse, Benjamin, de Oliveria Mann, Carina, Mears, Kepler, Liu, Jingjing, Intemann, Andrea, Schwede, Frank and Kranzusch, Philip (2023) cGLRs are a diverse family of pattern recognition receptors in innate immunity. Cell, 186 (15). 3261-3276.e20. ISSN 1097-4172

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.

Item Type:	Article
Keywords:	Humans Animals Nucleotidyltransferases Immunity, Innate Signal Transduction DNA Receptors, Pattern Recognition
Date Deposited:	01 Sep 2023 00:46
Last Modified:	01 Sep 2023 00:46
URI:	https://oak.novartis.com/id/eprint/48451