Cyclic GMP-AMP synthase-like receptor 1 (cGLR1) is a cytosolic cGAS-like nucleotidyltransferase of the Mab-21 family that functions as a pattern-recognition receptor for long double-stranded RNA. On binding dsRNA (longer than about 30 bp), it is allosterically activated to synthesize, from ATP and GTP and using Mg2+/Mn2+ as cofactor, the non-canonical cyclic dinucleotide second messenger 3',2'-cGAMP (also producing 2',3'-cGAMP and contributing to 2',3'-c-di-GMP synthesis during infection), through a two-step reaction via a linear pppA(2'-5')pG intermediate. The resulting cyclic dinucleotides bind and activate the innate-immune adaptor STING (dSTING), which signals through the NF-kappaB transcription factor Relish to drive an antiviral transcriptional response. cGLR1 is an invertebrate analog of vertebrate cGAS in the cGAS-STING antiviral pathway, tuned to sense viral RNA rather than DNA.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003725 double-stranded RNA binding | IDA PMID:34261127 cGAS-like receptors sense RNA and control 3'2'-cGAMP signall... | ACCEPT | Summary: cGLR1 was identified by a forward biochemical screen as a direct sensor of long double-stranded RNA; dsRNA binding activates its nucleotidyltransferase. This is a well-supported, specific and core molecular function. Reason: Direct experimental demonstration that cGLR1 is a dsRNA sensor and that long dsRNA (>30 bp) activates catalysis; this is the defining ligand-recognition function of the receptor. Supporting Evidence: PMID:34261127 used a forward biochemical screen to identify cGLR1 as a double-stranded RNA sensor in the model organism Drosophila melanogaster PMID:34261127 Dm-cGLR1 recognize dsRNAs longer than 30Β bp |
| GO:0003725 double-stranded RNA binding | IDA PMID:34261128 Two cGAS-like receptors induce antiviral immunity in Drosoph... | ACCEPT | Summary: Independent confirmation that cGLR1 is activated by double-stranded RNA. Duplicate of the dsRNA-binding annotation from PMID:34261127; both are valid. Reason: Holleufer et al. independently established cGLR1 as a dsRNA-activated receptor, corroborating the core ligand-binding function. Supporting Evidence: PMID:34261128 cGLR1 is activated by |
| GO:0005575 cellular_component | ND GO_REF:0000015 | ACCEPT | Summary: Root cellular component ND annotation: when it was made, no cellular component had been curated for this gene product from literature. Reason: ACCEPT under the ND acceptance rule (projects/NO_DATA.md). The evidence this review cites for the cellular component is inferred (from orthologs, family membership or sequence features) or comes from other species; none of it is literature on this gene product in this species. This was judged from the review's own content during the NO_DATA re-action pass, not from a new literature search. Earlier action: REMOVE. Re-checked 2026-10-31: PMID:34261127, cited in core_functions, characterizes cGLR1's RNA sensing and product, not its localization. Possibly stale: the 2026-11-06 ND citation pass found literature on this gene in this species that may identify a location; see cGlr1-notes.md, section "ND literature-search citations (2026-11-06)". A curator should check it before this ACCEPT stands. |
| GO:0005829 cytosol | IC PMID:34261128 Two cGAS-like receptors induce antiviral immunity in Drosoph... | ACCEPT | Summary: cGLR1 acts as a cytosolic sensor of cytoplasmic dsRNA and a cytosolic cyclic-dinucleotide synthase; the location is curator-inferred (IC) from its 3',2'-cGAMP synthase activity. Reason: The enzyme is a cytosolic pattern-recognition receptor detecting cytoplasmic dsRNA; the IC inference from its synthase activity is sound and matches the cytosolic site of cyclic-dinucleotide signalling. |
| GO:0043330 response to exogenous dsRNA | IDA PMID:34261127 cGAS-like receptors sense RNA and control 3'2'-cGAMP signall... | ACCEPT | Summary: cGLR1 directly responds to exogenous (viral) double-stranded RNA by producing 3',2'-cGAMP, a bona fide participant in the response to exogenous dsRNA. Reason: As the dsRNA sensor that transduces detection of exogenous dsRNA into a second-messenger signal, cGLR1 executes a step in this response. Supporting Evidence: PMID:34261127 We show that RNA recognition activates Drosophila cGLR1 to synthesize the novel product cG[3'-5']pA[2'-5']p (3'2'-cGAMP) |
| GO:0051607 defense response to virus | IMP PMID:34261127 cGAS-like receptors sense RNA and control 3'2'-cGAMP signall... | ACCEPT | Summary: cGLR1-derived 3',2'-cGAMP induces an enhanced antiviral state in vivo that protects flies from viral infection, establishing a core antiviral defense role through the dSTING-NF-kappaB pathway. Reason: Genetic/functional evidence links cGLR1 activity to protection from viral infection via dSTING and Relish; a core biological process for the gene. Supporting Evidence: PMID:34261127 3'2'-cGAMP induces an enhanced antiviral state PMID:34261127 Genetic mutations to Sting and the NF-ΞΊB homologue Relish ablated |
| GO:0051607 defense response to virus | IMP PMID:34261128 Two cGAS-like receptors induce antiviral immunity in Drosoph... | ACCEPT | Summary: Independent evidence that cGLR1 activates Sting- and NF-kappaB-dependent antiviral immunity against RNA and DNA viruses. Duplicate of the defense-response annotation; both are valid. Reason: Corroborates the core antiviral defense role of cGLR1. 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:37659413 The virus-induced cyclic dinucleotide 2'3'-c-di-GMP mediates... | ACCEPT | Summary: In addition to its signature 3',2'-cGAMP, cGLR1 also produces the 2',3' isomer; both cGAMP isomers were detected in the hemolymph of flies expressing active cGLR1 (and not the inactive mutant). Reason: Direct in vivo detection of 2',3'-cGAMP produced by active cGLR1 supports this catalytic activity, though 3',2'-cGAMP is the predominant/defining product. Supporting Evidence: PMID:37659413 only 2'3'-cGAMP and 3'2'-cGAMP were detected in the hemolymph of flies ectopically expressing cGLR1 |
| GO:0098586 cellular response to virus | IDA PMID:37659413 The virus-induced cyclic dinucleotide 2'3'-c-di-GMP mediates... | ACCEPT | Summary: Viral (DCV/Nora) infection triggers cGLR-dependent production of cyclic dinucleotides in Drosophila, placing cGLR1 within the cellular response to virus. Reason: cGLR1 catalytic output is induced by and required for the cyclic-dinucleotide response to viral infection, a direct participation in the cellular antiviral response. Supporting Evidence: PMID:37659413 systemic DCV infection resulted in the induction of 2β²3β²-cGAMP PMID:37659413 cGLR1 contributes to the production of 2β²3β²-c-di-GMP in the context of a viral infection in flies |
| GO:0140700 3',2'-cyclic GMP-AMP synthase activity | IDA PMID:34261127 cGAS-like receptors sense RNA and control 3'2'-cGAMP signall... | ACCEPT | Summary: The defining molecular function of cGLR1: dsRNA-activated synthesis of the novel cyclic dinucleotide 3',2'-cGAMP from ATP and GTP. Reason: Direct biochemical and structural demonstration that RNA recognition activates cGLR1 to synthesize 3',2'-cGAMP; the core catalytic activity. Supporting Evidence: PMID:34261127 We show that RNA recognition activates Drosophila cGLR1 to synthesize the novel product cG[3'-5']pA[2'-5']p (3'2'-cGAMP) |
| GO:0140700 3',2'-cyclic GMP-AMP synthase activity | IDA PMID:34261128 Two cGAS-like receptors induce antiviral immunity in Drosoph... | ACCEPT | Summary: Independent confirmation that dsRNA-activated cGLR1 produces 3',2'-cGAMP. Duplicate of the core synthase annotation; both are valid. Reason: Corroborates the signature 3',2'-cGAMP synthase activity of cGLR1. Supporting Evidence: PMID:34261128 cGLR1 is activated by |
| GO:0140700 3',2'-cyclic GMP-AMP synthase activity | IDA PMID:37659413 The virus-induced cyclic dinucleotide 2'3'-c-di-GMP mediates... | ACCEPT | Summary: Active cGLR1 produces 3',2'-cGAMP in vivo (detected in hemolymph of flies expressing catalytically active but not inactive cGLR1). Third independent support for the core synthase activity. Reason: In vivo detection of 3',2'-cGAMP dependent on catalytically active cGLR1 corroborates the signature synthase activity. Supporting Evidence: PMID:37659413 only 2'3'-cGAMP and 3'2'-cGAMP were detected in the hemolymph of flies ectopically expressing cGLR1 |
| GO:0140896 cGAS/STING signaling pathway | IDA PMID:37659413 The virus-induced cyclic dinucleotide 2'3'-c-di-GMP mediates... | ACCEPT | Summary: cGLR1 is the sensor/synthase arm of the invertebrate cGAS-STING pathway: its cyclic-dinucleotide products activate dSTING and downstream NF-kappaB (Relish) signalling. Reason: cGLR1 executes the initiating step (ligand sensing and second-messenger synthesis) of the cGAS/STING signalling pathway in Drosophila. Supporting Evidence: PMID:37659413 systemic DCV infection resulted in the induction of 2β²3β²-cGAMP |
| GO:0140896 cGAS/STING signaling pathway | IMP PMID:34261128 Two cGAS-like receptors induce antiviral immunity in Drosoph... | ACCEPT | Summary: Mutant/functional evidence that cGLR1 signalling is Sting-dependent. Duplicate of the cGAS/STING pathway annotation; both are valid. Reason: Corroborates cGLR1'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:34261127 cGAS-like receptors sense RNA and control 3'2'-cGAMP signall... | ACCEPT | Summary: cGLR1 is the dedicated dsRNA sensor that converts detection of exogenous (viral) dsRNA into an antiviral immune response through the dSTING-NF-kappaB axis. The dsRNA-specific framing is fully justified for cGLR1. Reason: cGLR1 directly links exogenous-dsRNA recognition to the innate immune response, executing the sensing step of this process. Supporting Evidence: PMID:34261127 used a forward biochemical screen to identify cGLR1 as a double-stranded RNA sensor in the model organism Drosophila melanogaster |
| GO:1902615 immune response involved in response to exogenous dsRNA | IMP PMID:34261128 Two cGAS-like receptors induce antiviral immunity in Drosoph... | ACCEPT | Summary: Independent support that cGLR1 mounts an antiviral immune response upon dsRNA/RNA-virus stimulation. Duplicate of the dsRNA immune-response annotation; both are valid for cGLR1. Reason: Corroborates cGLR1's role in the immune response to exogenous dsRNA. Supporting Evidence: PMID:34261128 We show that cGLR1 and cGLR2 activate Sting- and NF-ΞΊB-dependent antiviral |
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Download this section (compressed HTML)Q: What is the endogenous source and structure of the viral dsRNA recognized by cGLR1 during natural infection, and how is self versus non-self RNA discriminated?
Q: How is the balance between 3',2'-cGAMP, 2',3'-cGAMP and 2',3'-c-di-GMP outputs regulated, and what determines dSTING responsiveness to each?
Experiment: Structure-guided separation-of-function mutants that uncouple dsRNA binding from catalysis, tested for antiviral protection in vivo.
Experiment: Quantitative CDN metabolomics across a panel of RNA and DNA viruses in cGLR1 versus cGLR2 single and double mutants to define each receptor's contribution.
cGAS-like receptor 1 (cGlr1) encodes a receptor for double stranded RNA, a hallmark of viral replication in infected cells. It produces cyclic dinucleotide second messengers that activate the STING pathway.
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