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.
Yao Li  1 ,  Kailey M Slavik  2 ,  Hunter C Toyoda  2 ,  Benjamin R Morehouse  2 ,  Carina C de Oliveira Mann  3 ,  Anamaria Elek  4 ,  Shani Levy  4 ,  Zhenwei Wang  5 ,  Kepler S Mears  6 ,  Jingjing Liu  6 ,  Dmitry Kashin  7 ,  Ximing Guo  5 ,  Tali Mass  8 ,  Arnau Sebé-Pedrós  9 ,  Frank Schwede  7 ,  Philip J Kranzusch  10
Affiliations
  • 1. Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 2. Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 3. Institute of Virology, Technical University of Munich, 81675 Munich, Germany.
  • 4. Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
  • 5. Haskin Shellfish Research Laboratory, Department of Marine and Coastal Sciences, Rutgers University, Port Norris, NJ 08349, USA.
  • 6. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 7. Biolog Life Science Institute GmbH & Co. KG, Flughafendamm 9a, 28199 Bremen, Germany.
  • 8. Department of Marine Biology, The Leon H. Charney School of Marine Sciences, University of Haifa, Mt. Carmel, Haifa 3498838, Israel; Morris Kahn Marine Research Station, The Leon H. Charney School of Marine Sciences, University of Haifa, Sdot Yam, Israel.
  • 9. Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; ICREA, Barcelona, Spain.
  • 10. Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 37379839 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.

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