Journal
NATURE
Volume 597, Issue 7874, Pages 109-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-03743-5
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Funding
- Pew Biomedical Scholars program
- Burroughs Wellcome Fund PATH program
- Richard and Susan Smith Family Foundation
- Mathers Foundation
- Mark Foundation for Cancer Research
- Cancer Research Institute CLIP grant
- V Foundation V Scholar Award
- Parker Institute for Cancer Immunotherapy
- Agence Nationale de la Recherche [ANR-17-CE15-0014]
- Investissement d'Avenir Programme [ANR-10-LABX-0036, ANR-11-EQPX-0022]
- Institut Universitaire de France
- Chinese National Overseas Expertise Introduction Center for Discipline Innovation (Project '111') [D18010]
- Foreign Experts Program [2020A1414010306]
- Natural Science Foundation [32000662]
- Deutsche Forschungsgemeinschaft (DFG) [SPP1879, INST 192/524-1 FUGG]
- Charles A. King Trust Postdoctoral Fellowship
- Ruth L. Kirschstein NRSA Postdoctoral Fellow NIH [F32GM133063]
- US DOE Office of Science User Facility [DE-AC02-05CH11231]
- Argonne National Laboratory Advanced Photon Source [DE-AC02-06CH11357]
- ALS-ENABLE program
- NIGMS [P30 GM124169-01]
- Northeastern Collaborative Access Team [P30 GM124165, S10RR029205, S10OD021527]
- Agence Nationale de la Recherche (ANR) [ANR-11-EQPX-0022, ANR-10-LABX-0036] Funding Source: Agence Nationale de la Recherche (ANR)
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cGLRs are innate immune sensors capable of recognizing divergent molecular patterns and catalyzing synthesis of distinct nucleotide second messenger signals.
Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that produces the second messenger cG[2'-5']pA[3'-5']p (2'3'-cGAMP) and controls activation of innate immunity in mammalian cells(1-5). Animal genomes typically encode multiple proteins with predicted homology to cGAS(6-10), but the function of these uncharacterized enzymes is unknown. Here we show that cGAS-like receptors (cGLRs) are innate immune sensors that are capable of recognizing divergent molecular patterns and catalysing synthesis of distinct nucleotide second messenger signals. Crystal structures of human and insect cGLRs reveal a nucleotidyltransferase signalling core shared with cGAS and a diversified primary ligand-binding surface modified with notable insertions and deletions. We demonstrate that surface remodelling of cGLRs enables altered ligand specificity and used a forward biochemical screen to identify cGLR1 as a double-stranded RNA sensor in the model organism Drosophila melanogaster. We show that RNA recognition activates Drosophila cGLR1 to synthesize the novel product cG[3'-5']pA[2'-5']p (3'2'-cGAMP). A crystal structure of Drosophila stimulator of interferon genes (dSTING) in complex with 3'2'-cGAMP explains selective isomer recognition, and 3'2'-cGAMP induces an enhanced antiviral state in vivo that protects from viral infection. Similar to radiation of Toll-like receptors in pathogen immunity, our results establish cGLRs as a diverse family of metazoan pattern recognition receptors.
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