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

Cell. 2023 Jul 20;186(15):3261-3276.e20. doi: 10.1016/j.cell.2023.05.038. Epub 2023 Jun 27.


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.

Keywords: STING; cGAS; cGLR; cyclic dinucleotides; innate immunity; pattern recognition receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA / metabolism
  • Humans
  • Immunity, Innate* / genetics
  • Nucleotidyltransferases* / metabolism
  • Receptors, Pattern Recognition
  • Signal Transduction / genetics


  • Nucleotidyltransferases
  • DNA
  • Receptors, Pattern Recognition