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PreprintCited by 118interferon and immune responsesImmune Response and InflammationInvertebrate Immune Response Mechanisms

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

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Li, Yao, Slavik, Kailey M., Morehouse, Benjamin R., de Oliveira Mann, Carina C., Mears, Kepler, Liu, Jingjing, Kashin, Dmitry, Schwede, Frank, Kranzusch, Philip J.·2023·Cell
DOI 10.1101/2023.02.22.529553PMC PMC10527820

Preprint — published as 10.1016/j.cell.2023.05.038

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Abstract

Summary: cGAS (cyclic GMP-AMP synthase) 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 the protein STING and downstream immunity. Here we discover cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in animal innate immunity. Building on recent analysis in Drosophila , we use a bioinformatic approach to identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screen of 140 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of alternative nucleotide signals including isomers of cGAMP and cUMP-AMP. Using structural biology, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Together our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.

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Metadata

Authors
Li, Y., Slavik, K. M., Morehouse, B. R., de Oliveira Mann, C. C., Mears, K., Liu, J., Kashin, D., Schwede, F., & Kranzusch, P. J.
Affiliations
  • Harvard University (US)
  • Dana-Farber Cancer Institute (US)
  • Biolog Life Science Institute (DE)
Corresponding author
Kranzusch, Philip J.
ORCID
Venue
Cell
Publisher
openRxiv
Published
2023-02-22
Volume
186
Issue
15
Pages
3261-3276.e20
ISSN
0092-8674 (ISSN-L)
DOI
10.1101/2023.02.22.529553
PMC
PMC10527820
OpenAlex
W4382241824
Cited by
118
References
1
Citations by year
2026: 26 · 2025: 38 · 2024: 41 · 2023: 13
FWCI
12.82
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Cell (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (publishedVersion, cc-by)
  • PubMed Central (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • mediaTUM (Technical University of Munich) (submittedVersion)
  • The Novartis Repository (Novartis) (submittedVersion)
Funders
  • U.S. Department of Agriculture
  • Burroughs Wellcome Fund (P30 GM124165)
  • Cancer Research Institute
  • Richard and Susan Smith Family Foundation
  • Dana-Farber Cancer Institute
  • G. Harold and Leila Y. Mathers Foundation (P30 GM124165)
  • Parker Institute for Cancer Immunotherapy (P30 GM124165)
  • Mark Foundation For Cancer Research (P30 GM124165)
  • Ministerio de Ciencia e Innovación
  • National Institutes of Health (1dp2gm146250-01, 1s10od021527-01, DE-AC02–06CH11357, GM124165)
  • National Cancer Institute (DE-AC02-06CH11357, F99CA274660)
  • National Institute of General Medical Sciences (F32GM133063, DP2 GM146250, P30GM124165)
  • National Center for Research Resources (S10RR029205)
  • Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, 06CH11357, P30 GM124165)
  • H2020 European Research Council (851647)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › Invertebrate Immune Response Mechanisms
Keywords
cGAS, pattern recognition receptors, innate immunity, STING signaling, cGAMP, c-di-AMP, nucleotide signaling, cytosolic DNA sensing, double-stranded RNA, immune system evolution, Drosophila, coral, oysters, metazoan phylogeny

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