Li, Y., Slavik, K.M., Toyoda, H.C., Morehouse, B.R., de Oliveira Mann, C.C., Elek, A., Levy, S., Wang, Z., Mears, K.S., Liu, J., Kashin, D., Guo, X., Mass, T., Sebé-Pedrós, A., Schwede, F., Kranzusch, P.J. (2023). cGLRs are a diverse family of pattern recognition receptors in innate immunity.  Cell 186(15): 3261--3276.e20.

FBrf0257104

Research paper

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.

PMC10527820 (PMC) (EuropePMC)