Drosophila Sting (dSTING, CG1667) is the single fly ortholog of the STING family and a multi-pass endoplasmic reticulum membrane protein that acts as an innate-immune signaling adapter. It directly binds cyclic dinucleotides - bacterial cyclic di-GMP and the virus-induced cyclic GMP-AMP isomers 3'2'-cGAMP (its preferred ligand) and 2'3'-cGAMP that are synthesized by the cGAS-like receptors cGLR1 and cGLR2 in response to RNA/DNA virus infection. Ligand binding drives dSTING oligomerization (via a cryptic RHIM motif) and activation of the NF-kappaB transcription factor Relish through the IMD pathway kinase dIKKbeta. Because insects lack type I interferons and the TBK1-IRF3-IFN axis, dSTING signals to NF-kappaB rather than to interferon, inducing antimicrobial peptides and antiviral genes. It mediates defense against bacteria (Listeria monocytogenes, Coxiella burnetii) and a broad range of viruses, and in the adult brain restricts Zika virus by inducing autophagy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000045 autophagosome assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) transfer of the ancestral STING autophagy function. dSTING does induce autophagy in a physiological context (Zika virus in the brain), but the specific autophagosome-assembly step reflects the mammalian STING/ERGIC-LC3 mechanism rather than a fly-specific demonstration; kept as a non-core, inherited annotation. Reason: The IBD node placement is sound - dSTING falls within the STING clade that has an autophagy role, and Drosophila dSTING does drive autophagy against Zika virus. However, autophagy is a context-specific, non-core function for dSTING relative to its central cyclic-dinucleotide sensing / NF-kappaB (Relish) signaling role, and the precise assembly step is not directly demonstrated in the fly. Supporting Evidence: PMID:29934091 inducing autophagy in the brain. |
| GO:0002218 activation of innate immune response | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic mapping from the STING domain (IPR029158). dSTING is genuinely an activator of the innate immune response (NF-kappaB/Relish, AMPs, antiviral genes), so this broad term is correct for the fly. Reason: Multiple experimental studies show dSTING activates innate immune signaling; the term is broad but accurate and taxonomically appropriate (it does not assert an interferon output). Supporting Evidence: PMID:29924997 DmSTING retains its ability to bind cyclic di-GMP, leading to the induction of innate immune response genes. |
| GO:0002807 positive regulation of antimicrobial peptide biosynthetic process | IMP PMID:29924997 Analysis of Drosophila STING Reveals an Evolutionarily Conse... | ACCEPT | Summary: Experimental (IMP) annotation: dSTING overexpression increases antimicrobial peptide induction and dSTING knockdown reduces it during Listeria infection, acting through the IMD pathway and Relish. Reason: Directly supported by loss- and gain-of-function experiments in flies; a core downstream output of dSTING signaling. Supporting Evidence: PMID:29924997 overexpression of dmSTING led to increased antimicrobial peptide induction and activation of the Drosophila NF-ΞΊB homolog Relish. PMID:29924997 epistasis analysis in flies indicated that dmSTING functioned predominantly through the IMD pathway and Relish to achieve antimicrobial peptide induction. |
| GO:0005776 autophagosome | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) localization to the autophagosome, inherited from the mammalian STING autophagy function. dSTING's primary and experimentally demonstrated location is the ER membrane; the autophagosome association is inherited and non-core. Reason: Consistent with the ancestral autophagy role, but the fly protein's demonstrated steady-state location is the ER membrane; autophagosome activity is context-specific and not a core localization for dSTING. |
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of the ER membrane as the site of STING activity, matching the experimentally determined location of dSTING. The fly gene appears in its own WITH/FROM (FBgn0033453), reflecting experimental grounding on the target itself. Reason: The ER membrane is the demonstrated location of dSTING and is conserved across the family; a core localization annotation. Supporting Evidence: PMID:30119996 co-localize with the endoplasmic reticulum (ER) marker calnexin |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:30119996 The Kinase IKKΞ² Regulates a STING- and NF-ΞΊB-Dependent Antiv... | ACCEPT | Summary: Direct experimental (IDA) demonstration that dSTING localizes to the ER membrane; dSTING shows a vesicular pattern in S2 cells and co-localizes with the ER marker calnexin. UniProt cites this reference for the ER membrane subcellular location. Reason: Experimentally established core localization of dSTING. Supporting Evidence: PMID:30119996 co-localize with the endoplasmic reticulum (ER) marker calnexin |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic mapping from the UniProt Subcellular Location vocabulary (SL-0097, ER membrane), consistent with the experimental IDA annotation. Reason: Correctly reflects the curated ER membrane localization of dSTING. |
| GO:0016239 positive regulation of macroautophagy | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) transfer of positive regulation of macroautophagy, corroborated in the fly by the experimental IDA annotation (PMID:29934091). The target appears in its own WITH/FROM, reflecting experimental grounding on dSTING itself. Reason: dSTING promotes autophagy in the adult brain to restrict Zika virus, consistent with the conserved ancestral autophagy-promoting role; a genuine (though context-specific) function. Supporting Evidence: PMID:29934091 inducing autophagy in the brain. |
| GO:0016239 positive regulation of macroautophagy | IDA PMID:29934091 Inflammation-Induced, STING-Dependent Autophagy Restricts Zi... | ACCEPT | Summary: Direct experimental (IDA) evidence that dSTING induces autophagy in the Drosophila brain to restrict Zika virus infection. Reason: Loss of dSTING reduces, and its induction increases, protective autophagy against ZIKV in the brain; a directly demonstrated function. Supporting Evidence: PMID:29934091 inducing autophagy in the brain. |
| GO:0032481 positive regulation of type I interferon production | IEA GO_REF:0000002 | REMOVE | Summary: InterPro2GO electronic mapping from the STING domain (IPR029158) to type I interferon production. This is taxonomically inappropriate for Drosophila, which has no type I interferons and no TBK1-IRF3-IFN axis; dSTING instead signals to NF-kappaB (Relish). Reason: Insects lack type I interferons entirely, so dSTING cannot regulate their production. Every experimental study of dSTING shows an NF-kappaB (Relish)-dependent, interferon-independent output; the authors explicitly note that this antiviral program predates the emergence of interferons in vertebrates. This is a demonstrably wrong over-propagated electronic mapping that should be removed on biological/taxonomic grounds. Supporting Evidence: PMID:33262294 regulates an NF-ΞΊB-dependent antiviral program that predates the emergence of |
| GO:0035438 cyclic-di-GMP binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) transfer of cyclic di-GMP binding, corroborated by direct experimental binding data in the fly (PMID:29924997). The fly gene appears in its own WITH/FROM. Reason: c-di-GMP binding is a conserved, experimentally demonstrated molecular function of dSTING and a core activity. Supporting Evidence: PMID:29924997 DmSTING retains its ability to bind cyclic di-GMP, leading to the induction of innate immune response genes. |
| GO:0035438 cyclic-di-GMP binding | IDA PMID:29924997 Analysis of Drosophila STING Reveals an Evolutionarily Conse... | ACCEPT | Summary: Direct experimental (IDA) demonstration that dSTING binds bacterial cyclic di-GMP, leading to induction of innate immune response genes. Reason: Core, directly demonstrated ligand-binding activity of dSTING. Supporting Evidence: PMID:29924997 DmSTING retains its ability to bind cyclic di-GMP, leading to the induction of innate immune response genes. |
| GO:0035438 cyclic-di-GMP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic mapping (STING_C, IPR033952) to cyclic di-GMP binding, consistent with the experimental IDA annotation. Reason: Correctly reflects the demonstrated c-di-GMP binding activity of dSTING. |
| GO:0042742 defense response to bacterium | IMP PMID:29924997 Analysis of Drosophila STING Reveals an Evolutionarily Conse... | ACCEPT | Summary: Experimental (IMP) annotation: dSTING knockdown increases Listeria monocytogenes burden and host mortality, establishing a role in antibacterial defense. Reason: Directly demonstrated by loss- and gain-of-function during Listeria infection; a core function. Supporting Evidence: PMID:29924997 overexpression of dmSTING led to increased antimicrobial peptide induction and activation of the Drosophila NF-ΞΊB homolog Relish. |
| GO:0045087 innate immune response | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) transfer of the general innate immune response term, well supported by the fly experimental literature. The target appears in its own WITH/FROM. Reason: dSTING is a central innate immune signaling adapter in Drosophila; this broad term is correct though less informative than the specific antiviral/antibacterial terms. Supporting Evidence: PMID:29924997 DmSTING retains its ability to bind cyclic di-GMP, leading to the induction of innate immune response genes. |
| GO:0051607 defense response to virus | IDA PMID:33262294 2'3'-cGAMP triggers a STING- and NF-ΞΊB-dependent broad antiv... | ACCEPT | Summary: Direct experimental (IDA) evidence that dSTING mediates a broad antiviral response triggered by 2'3'-cGAMP, dependent on NF-kappaB (Relish) and independent of interferons. Reason: Core antiviral function of dSTING, directly demonstrated against multiple viruses. Supporting Evidence: PMID:33262294 regulates an NF-ΞΊB-dependent antiviral program that predates the emergence of |
| GO:0051607 defense response to virus | IDA PMID:34261128 Two cGAS-like receptors induce antiviral immunity in Drosoph... | ACCEPT | Summary: Direct experimental (IDA) evidence that dSTING mediates antiviral immunity downstream of the cGAS-like receptors cGLR1/cGLR2 in response to RNA or DNA virus infection. Reason: Core, directly demonstrated antiviral defense function. Supporting Evidence: PMID:34261128 cGLR1 and cGLR2 activate |
| GO:0051607 defense response to virus | IMP PMID:29934091 Inflammation-Induced, STING-Dependent Autophagy Restricts Zi... | ACCEPT | Summary: Experimental (IMP) evidence that dSTING restricts Zika virus infection of the Drosophila brain. Reason: Loss of dSTING increases ZIKV infection and host death; a directly demonstrated antiviral defense function. Supporting Evidence: PMID:29934091 inducing autophagy in the brain. |
| GO:0051607 defense response to virus | IMP PMID:30119996 The Kinase IKKΞ² Regulates a STING- and NF-ΞΊB-Dependent Antiv... | ACCEPT | Summary: Experimental (IMP) evidence that dSTING controls infection by picorna-like viruses, acting upstream of the kinase dIKKbeta to regulate the antiviral factor Nazo. Reason: Directly demonstrated antiviral defense function; core. Supporting Evidence: PMID:30119996 acting upstream of dIKKΞ² to regulate |
| GO:0051607 defense response to virus | IMP PMID:34261127 cGAS-like receptors sense RNA and control 3'2'-cGAMP signall... | ACCEPT | Summary: Experimental (IMP) evidence that dSTING, activated by cGLR1-derived 3'2'-cGAMP, induces an enhanced antiviral state in vivo that protects from viral infection. Reason: Directly demonstrated antiviral defense function; core. Supporting Evidence: PMID:34261127 selective isomer recognition, and 3'2'-cGAMP induces an enhanced antiviral state |
| GO:0061507 2',3'-cyclic GMP-AMP binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) transfer of 2',3'-cGAMP binding, corroborated by the fly experimental IDA annotation. dSTING binds 2'3'-cGAMP (produced by cGLR2), although it prefers 3'2'-cGAMP. Reason: Conserved and experimentally supported cyclic-dinucleotide binding activity; core molecular function. Supporting Evidence: PMID:34261128 cGLR1 and cGLR2 activate |
| GO:0061507 2',3'-cyclic GMP-AMP binding | IDA PMID:33262294 2'3'-cGAMP triggers a STING- and NF-ΞΊB-dependent broad antiv... | ACCEPT | Summary: Direct experimental (IDA) evidence that dSTING binds/responds to 2'3'-cGAMP, triggering the NF-kappaB-dependent antiviral response. Reason: Directly demonstrated ligand-binding activity; core molecular function. Supporting Evidence: PMID:33262294 regulates an NF-ΞΊB-dependent antiviral program that predates the emergence of |
| GO:0061709 reticulophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) transfer of reticulophagy (ER-phagy) from the mammalian STING autophagy function. The fly has a demonstrated general autophagy role (Zika brain) but reticulophagy specifically has not been shown in Drosophila; retained as a non-core inherited annotation. Reason: The IBD node placement is reasonable (dSTING is within the STING autophagy clade), but the specific ER-phagy process is not directly demonstrated in the fly and is peripheral to dSTING's core cyclic-dinucleotide sensing / NF-kappaB signaling role. |
| GO:0098586 cellular response to virus | IDA PMID:37659413 The virus-induced cyclic dinucleotide 2'3'-c-di-GMP mediates... | ACCEPT | Summary: Direct experimental (IDA) evidence that dSTING mediates a cellular antiviral response to the virus-induced cyclic dinucleotide 2'3'-c-di-GMP, a more potent dSTING agonist than cGAMP. Reason: Directly demonstrated cellular response to virus via cyclic-dinucleotide sensing; core. Supporting Evidence: PMID:37659413 This CDN was a more potent STING agonist than cGAMP in |
| GO:0140367 antibacterial innate immune response | IMP PMID:38363133 Drosophila melanogaster Sting mediates Coxiella burnetii inf... | ACCEPT | Summary: Experimental (IMP) evidence that dSTING protects against the Gram-negative bacterium Coxiella burnetii; Sting-null flies show higher mortality and reduced antimicrobial peptide induction. Reason: Directly demonstrated antibacterial innate immune function; core. Supporting Evidence: PMID:38363133 reduced induction of antimicrobial |
| GO:0140374 antiviral innate immune response | IMP PMID:33262294 2'3'-cGAMP triggers a STING- and NF-ΞΊB-dependent broad antiv... | ACCEPT | Summary: Experimental (IMP) evidence that dSTING drives an NF-kappaB (Relish)-dependent antiviral program in response to 2'3'-cGAMP. Reason: Core antiviral innate immune function, directly demonstrated. Supporting Evidence: PMID:33262294 regulates an NF-ΞΊB-dependent antiviral program that predates the emergence of |
| GO:0140374 antiviral innate immune response | IMP PMID:34965418 Orally acquired cyclic dinucleotides drive dSTING-dependent ... | ACCEPT | Summary: Experimental (IMP) evidence that orally acquired cyclic dinucleotides drive dSTING- and dTBK1-dependent, NF-kappaB-dependent antiviral immunity in gut enterocytes. Reason: Core antiviral innate immune function in a tissue-specific (enterocyte) context, directly demonstrated. Supporting Evidence: PMID:34965418 leading to NF-kB-dependent gene expression. |
| GO:0140374 antiviral innate immune response | IMP PMID:38969190 A cryptic homotypic interaction motif of insect STING is req... | ACCEPT | Summary: Experimental (IMP) evidence that a cryptic RHIM (cRHIM) motif is required for dSTING oligomerization and antiviral signaling; cRHIM-deficient cells show higher viral load and weaker Relish activation. Reason: Directly demonstrated requirement for dSTING in antiviral innate immune signaling; core. Supporting Evidence: PMID:38969190 essential for its antiviral |
| GO:0140460 response to Gram-negative bacterium | IMP PMID:38363133 Drosophila melanogaster Sting mediates Coxiella burnetii inf... | ACCEPT | Summary: Experimental (IMP) evidence that dSTING responds to the Gram-negative bacterium Coxiella burnetii, limiting infection by reducing reactive oxygen species accumulation. Reason: Directly demonstrated response to a Gram-negative bacterium; a specific and accurate term. Supporting Evidence: PMID:38363133 reduced induction of antimicrobial |
| GO:0140704 3',2'-cyclic GMP-AMP binding | IDA PMID:34261127 cGAS-like receptors sense RNA and control 3'2'-cGAMP signall... | ACCEPT | Summary: Direct experimental (IDA) evidence, including a co-crystal structure, that dSTING binds 3'2'-cGAMP (produced by cGLR1 from double-stranded RNA), its preferred cyclic-dinucleotide ligand. Reason: Structurally and biochemically demonstrated binding of the physiologically preferred ligand; a defining core molecular function of dSTING. Supporting Evidence: PMID:34261127 selective isomer recognition, and 3'2'-cGAMP induces an enhanced antiviral state |
| GO:0140704 3',2'-cyclic GMP-AMP binding | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS) transfer of 3',2'-cGAMP binding from the structurally characterized ligand-binding residues, consistent with the experimental IDA annotation and UniProt binding features. Reason: Reinforces the experimentally established 3'2'-cGAMP binding activity; correct. |
| GO:0140896 cGAS/STING signaling pathway | IDA PMID:37659413 The virus-induced cyclic dinucleotide 2'3'-c-di-GMP mediates... | ACCEPT | Summary: Direct experimental (IDA) evidence that dSTING is the central node of the cGLR-STING (cGAS/ STING) signaling pathway responding to the virus-induced CDN 2'3'-c-di-GMP. Reason: dSTING is by definition the STING component of this pathway; directly demonstrated. Core. Supporting Evidence: PMID:37659413 This CDN was a more potent STING agonist than cGAMP in |
| GO:0140896 cGAS/STING signaling pathway | IDA PMID:38969190 A cryptic homotypic interaction motif of insect STING is req... | ACCEPT | Summary: Direct experimental (IDA) evidence for dSTING's role in cGAS/STING signaling, mediated by its cryptic RHIM motif that drives oligomerization and downstream activation. Reason: dSTING is the STING component of the pathway; directly demonstrated. Core. Supporting Evidence: PMID:38969190 essential for its antiviral |
| GO:0140896 cGAS/STING signaling pathway | IMP PMID:29924997 Analysis of Drosophila STING Reveals an Evolutionarily Conse... | ACCEPT | Summary: Experimental (IMP) evidence placing dSTING in the cGAS/STING signaling pathway; dSTING binds cyclic dinucleotides to activate downstream Relish/IMD signaling. Reason: Core pathway membership, directly demonstrated by loss/gain-of-function. Supporting Evidence: PMID:29924997 DmSTING retains its ability to bind cyclic di-GMP, leading to the induction of innate immune response genes. |
| GO:0140896 cGAS/STING signaling pathway | IMP PMID:30119996 The Kinase IKKΞ² Regulates a STING- and NF-ΞΊB-Dependent Antiv... | ACCEPT | Summary: Experimental (IMP) evidence that dSTING signals within the cGAS/STING pathway, acting upstream of dIKKbeta and Relish to control picorna-like virus infection. Reason: Core pathway membership, directly demonstrated. Supporting Evidence: PMID:30119996 acting upstream of dIKKΞ² to regulate |
| GO:0140896 cGAS/STING signaling pathway | IMP PMID:33262294 2'3'-cGAMP triggers a STING- and NF-ΞΊB-dependent broad antiv... | ACCEPT | Summary: Experimental (IMP) evidence that dSTING, activated by 2'3'-cGAMP, drives the NF-kappaB-dependent branch of the cGAS/STING signaling pathway. Reason: Core pathway membership, directly demonstrated. Supporting Evidence: PMID:33262294 regulates an NF-ΞΊB-dependent antiviral program that predates the emergence of |
| GO:0140896 cGAS/STING signaling pathway | IMP PMID:34261127 cGAS-like receptors sense RNA and control 3'2'-cGAMP signall... | ACCEPT | Summary: Experimental (IMP) evidence that dSTING functions in the cGAS/STING signaling pathway, activated by cGLR1-derived 3'2'-cGAMP to induce an antiviral state. Reason: Core pathway membership, directly demonstrated. Supporting Evidence: PMID:34261127 selective isomer recognition, and 3'2'-cGAMP induces an enhanced antiviral state |
| GO:0140896 cGAS/STING signaling pathway | IMP PMID:34261128 Two cGAS-like receptors induce antiviral immunity in Drosoph... | ACCEPT | Summary: Experimental (IMP) evidence placing dSTING downstream of the cGAS-like receptors cGLR1/cGLR2 in the cGAS/STING signaling pathway. Reason: Core pathway membership, directly demonstrated. Supporting Evidence: PMID:34261128 cGLR1 and cGLR2 activate |
| GO:0140896 cGAS/STING signaling pathway | IMP PMID:34965418 Orally acquired cyclic dinucleotides drive dSTING-dependent ... | ACCEPT | Summary: Experimental (IMP) evidence that dSTING functions in cGAS/STING (CDN-STING-NF-kappaB) signaling in gut enterocytes in response to orally acquired cyclic dinucleotides. Reason: Core pathway membership in a tissue-specific context, directly demonstrated. Supporting Evidence: PMID:34965418 leading to NF-kB-dependent gene expression. |
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Download this section (compressed HTML)Q: Does dSTING physically nucleate the Relish/IMD signaling complex (e.g. via its cryptic RHIM motif and interaction with IMD), and could a more informative molecular-function term for a signaling-adapter/scaffold activity be assigned in addition to the cyclic-dinucleotide binding activities?
Q: Is the autophagy-promoting activity of dSTING mechanistically the same ERGIC/LC3-lipidation process as mammalian STING, or does the fly use a distinct route? This bears on whether the inherited autophagosome/reticulophagy annotations should be upgraded to experimental or remain inherited/non-core.
Experiment: Quantitative CDN-binding and dSTING-activation assays (e.g. thermophoresis/ITC plus reporter activation) comparing 3'2'-cGAMP, 2'3'-cGAMP, c-di-GMP and 2'3'-c-di-GMP to define the in vivo ligand hierarchy and the residues responsible for isomer selectivity.
Experiment: Tissue-resolved epistasis (enterocyte, fat body, brain) placing dSTING relative to dIKKbeta, Relish and dTBK1 to map which downstream branch (AMP induction, Nazo/antiviral genes, autophagy) dominates in each context.
Sting (Sting) encodes a signaling molecule functioning primarily in antiviral immunity. It is activated by cyclic dinucleotides produced by cGAS-like receptors or by bacteria.
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