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

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)3261-3276.e20
Issue number15
StatePublished - 20 Jul 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)


  • cGAS
  • cGLR
  • cyclic dinucleotides
  • innate immunity
  • pattern recognition receptor

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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