Cyclic GMP-AMP synthase-like receptor 2 (cGLR2) is a cytosolic cGAS-like nucleotidyltransferase of the Mab-21 family that contributes to antiviral innate immunity in Drosophila. On activation by a nucleic-acid ligand (double-stranded RNA enhances its activity), it synthesizes from ATP and GTP a range of cyclic dinucleotide second messengers, including 2',3'-cGAMP, 3',2'-cGAMP and, distinctively, 2',3'-c-di-GMP. These cyclic dinucleotides bind and activate the innate-immune adaptor STING (dSTING) and the downstream NF-kappaB transcription factor Relish, driving an antiviral transcriptional response. cGLR2 acts alongside cGLR1 as part of the invertebrate cGAS-STING pathway, expanding the repertoire of cyclic dinucleotide signals beyond 2',3'-cGAMP.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003725 double-stranded RNA binding | IDA PMID:37659413 The virus-induced cyclic dinucleotide 2'3'-c-di-GMP mediates... | ACCEPT | Summary: cGLR2 acts as a nucleic-acid sensor whose cyclic-dinucleotide synthesis is enhanced by double-stranded RNA; structure-guided modelling supports a conserved dsRNA-binding surface. Note the strongest in vitro binding/structural data are for cGLR2 orthologs and the endogenous activating ligand of D. melanogaster cGLR2 remains formally unidentified. Reason: The paper demonstrates dsRNA-facilitated activity and models cGLR2 as a nucleic-acid sensor, supporting a dsRNA-binding molecular function; retained despite the residual uncertainty over the endogenous ligand, consistent with not overruling an experimental (IDA) annotation. Supporting Evidence: PMID:37659413 activation is enhanced most strongly in the presence of dsRNA PMID:37659413 providing a structural explanation for the role of cGLR2 as a nucleic acid sensor |
| GO:0005829 cytosol | IC PMID:34261128 Two cGAS-like receptors induce antiviral immunity in Drosoph... | ACCEPT | Summary: cGLR2 is a cytosolic cyclic-dinucleotide synthase; the location is curator-inferred (IC) from its cGAMP synthase activities, consistent with cytosolic cGAS-like sensing. Reason: As a cytosolic cGAS-like nucleotidyltransferase producing second messengers, the IC inference to cytosol from its synthase activities is appropriate. |
| GO:0051607 defense response to virus | IMP PMID:34261128 Two cGAS-like receptors induce antiviral immunity in Drosoph... | ACCEPT | Summary: cGLR2 activates Sting- and NF-kappaB-dependent antiviral immunity against RNA and DNA viruses, establishing a core antiviral defense role. Reason: Functional/mutant evidence links cGLR2 to Sting/NF-kappaB-dependent antiviral immunity; a core process for the gene. Supporting Evidence: PMID:34261128 We show that cGLR1 and cGLR2 activate Sting- and NF-ΞΊB-dependent antiviral |
| GO:0061501 2',3'-cyclic GMP-AMP synthase activity | IDA PMID:34261128 Two cGAS-like receptors induce antiviral immunity in Drosoph... | ACCEPT | Summary: cGLR2 produces a combination of 2',3'-cGAMP and 3',2'-cGAMP; the 2',3'-cGAMP synthase activity is a core catalytic function (EC 2.7.7.86). Reason: Direct demonstration that cGLR2 produces 2',3'-cGAMP supports this catalytic activity. Supporting Evidence: PMID:34261128 produces a combination of 2'3'-cGAMP and 3'2'-cGAMP in response to an |
| GO:0061501 2',3'-cyclic GMP-AMP synthase activity | IDA PMID:37659413 The virus-induced cyclic dinucleotide 2'3'-c-di-GMP mediates... | ACCEPT | Summary: Flies expressing catalytically active cGLR2 accumulate both cGAMP isomers (plus 2',3'-c-di-GMP and 2',3'-c-di-AMP) in hemolymph, confirming 2',3'-cGAMP synthase activity in vivo. Independent support for the same activity. Reason: In vivo detection of both cGAMP isomers dependent on active cGLR2 corroborates the 2',3'-cGAMP synthase activity. Supporting Evidence: PMID:37659413 All the CDNs, including both cGAMP isomers, 2'3'-c-di-GMP and 2'3'-c-di-AMP, were detected in the hemolymph of flies ectopically expressing cGLR2 |
| GO:0061501 2',3'-cyclic GMP-AMP synthase activity | IEA GO_REF:0000003 | ACCEPT | Summary: Electronic annotation via EC 2.7.7.86 (2',3'-cGAMP synthase) mapping. Consistent with the experimentally assigned EC number for cGLR2 and with the IDA annotations for the same activity. Reason: The EC 2.7.7.86 -> GO mapping matches the curated EC number and experimentally demonstrated activity; the electronic annotation is correct. |
| GO:0098586 cellular response to virus | IDA PMID:37659413 The virus-induced cyclic dinucleotide 2'3'-c-di-GMP mediates... | ACCEPT | Summary: Viral (DCV) infection triggers cGLR-dependent production of cyclic dinucleotides, placing cGLR2 within the cellular response to virus. Reason: cGLR2 catalytic output contributes to the virus-induced cyclic-dinucleotide response, a direct participation in the cellular antiviral response. Supporting Evidence: PMID:37659413 systemic DCV infection resulted in the induction of 2β²3β²-cGAMP |
| GO:0140700 3',2'-cyclic GMP-AMP synthase activity | IDA PMID:34261128 Two cGAS-like receptors induce antiviral immunity in Drosoph... | ACCEPT | Summary: cGLR2 produces 3',2'-cGAMP in addition to 2',3'-cGAMP, so it also has 3',2'-cGAMP synthase activity. Reason: Direct demonstration that cGLR2 produces 3',2'-cGAMP supports this catalytic activity. Supporting Evidence: PMID:34261128 produces a combination of 2'3'-cGAMP and 3'2'-cGAMP in response to an |
| GO:0140896 cGAS/STING signaling pathway | IDA PMID:37659413 The virus-induced cyclic dinucleotide 2'3'-c-di-GMP mediates... | ACCEPT | Summary: cGLR2 is a sensor/synthase arm of the invertebrate cGAS-STING pathway; its cyclic-dinucleotide products (notably 2',3'-c-di-GMP) activate dSTING. Reason: cGLR2 executes the second-messenger-producing step of the cGAS/STING pathway in Drosophila. Supporting Evidence: PMID:37659413 we confirmed that 2β²3β²-c-di-GMP is major product of Drosophila cGLR2 |
| GO:0140896 cGAS/STING signaling pathway | IMP PMID:34261128 Two cGAS-like receptors induce antiviral immunity in Drosoph... | ACCEPT | Summary: Mutant/functional evidence that cGLR2 signalling is Sting-dependent. Duplicate of the cGAS/STING pathway annotation; both are valid. Reason: Corroborates cGLR2's participation in the cGAS/STING signalling pathway. Supporting Evidence: PMID:34261128 We show that cGLR1 and cGLR2 activate Sting- and NF-ΞΊB-dependent antiviral |
| GO:1902615 immune response involved in response to exogenous dsRNA | IMP PMID:34261128 Two cGAS-like receptors induce antiviral immunity in Drosoph... | MARK AS OVER ANNOTATED | Summary: This term asserts a dsRNA-specific trigger. That framing is firmly established for cGLR1 (the dedicated dsRNA sensor) but not for cGLR2: the source paper itself states cGLR2's activating stimulus was unidentified, and dsRNA-facilitation of cGLR2 was shown later (Cai et al. 2023) mainly in orthologs. cGLR2's antiviral role is better captured by the retained GO:0051607, GO:0140896 and GO:0098586 terms. Reason: The dsRNA-specificity encoded by this term overreaches for cGLR2, whose endogenous activating ligand remains unresolved; the annotation is not clearly wrong (dsRNA does facilitate cGLR2 activity) but represents an over-annotation relative to the evidence for this gene, whereas it is fully justified for cGLR1. Supporting Evidence: PMID:34261128 produces a combination of 2'3'-cGAMP and 3'2'-cGAMP in response to an PMID:37659413 The ligand activating cGLR2 is still unknown |
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Download this section (compressed HTML)Q: What is the endogenous ligand that activates D. melanogaster cGLR2 in vivo, and is dsRNA the physiological trigger or only one of several activating nucleic acids?
Q: What is the biological role of the distinctive cGLR2 product 2',3'-c-di-GMP relative to the cGAMP isomers in dSTING activation, and how do cGLR1 and cGLR2 divide labor during infection?
Experiment: Identify the physiological cGLR2 activator by crosslinking/immunoprecipitation of cGLR2-associated nucleic acids from virus-infected D. melanogaster, with in vitro reconstitution of activity.
Experiment: Compare antiviral protection and CDN profiles of cGLR2 catalytic and ligand-binding mutants against a panel of RNA and DNA viruses, in cGLR1/cGLR2 single and double mutant backgrounds.
cGAS-like receptor 2 (cGlr2) encodes a receptor sensing viral infections. It produces cyclic dinucleotide second messengers that activate the STING pathway.
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