DCAR-1 (DihydroCaffeic Acid Receptor 1) is a seven-transmembrane, class A (rhodopsin-like) G protein-coupled receptor of Caenorhabditis elegans that acts in two distinct tissues. In the epidermis it is a plasma-membrane receptor, localized to the apical surface of the hyp7 syncytium, that senses the endogenous tyrosine-derived metabolite 4-hydroxyphenyllactic acid (HPLA), a damage-associated molecular pattern produced upon fungal infection and wounding, and triggers antimicrobial peptide (nlp-29 cluster) gene expression through a Galpha (GPA-12) / p38 MAP kinase (TIR-1, NSY-1, SEK-1, PMK-1) / STA-2 signalling cassette, conferring resistance to the natural fungal pathogen Drechmeria coniospora. In sensory neurons (ASH, ASI, PVQ) the same receptor detects the exogenous water-soluble repellent dihydrocaffeic acid (DHCA) and mediates an avoidance response, acting with the TRPV channel subunits OCR-2 and OSM-9. DCAR-1 thus couples small-molecule (catecholic/phenolic acid) ligand detection to Galpha signalling, with clearly recognizable homologs restricted to nematode genomes.
Definition: Combining with the tyrosine-derived metabolite 4-hydroxyphenyllactic acid (HPLA), a damage-associated molecular pattern, to initiate a change in cell activity, typically via coupling to a heterotrimeric G protein. Applies to GPCRs, such as nematode DCAR-1, that detect HPLA (and structurally related catecholic/phenolic acids) to trigger downstream signalling.
Justification: DCAR-1's specific molecular function - detection of the small-molecule DAMP HPLA - can currently only be annotated with the generic parent G protein-coupled receptor activity (GO:0004930). No ontology term expresses the ligand-specific activity, leaving the receptor's most distinctive feature un-annotatable (an ontology gap).
Parent term: G protein-coupled receptor activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000104 | ACCEPT | Summary: DCAR-1 is a bona fide seven-transmembrane class A GPCR (7 predicted TM helices; PROSITE G_PROTEIN_RECEP_F1_2; PANTHER PTHR24243) that functions as a receptor for small-molecule ligands: HPLA in the epidermis and DHCA in sensory neurons, in both cases coupling to Galpha signalling. Reason: The GPCR activity is directly supported experimentally. DCAR-1 was identified as a heterologously expressible receptor for DHCA and shown to respond to HPLA, and it signals via the Galpha protein GPA-12. This is a core molecular function of the gene. Supporting Evidence: PMID:22090488 we identified a candidate dihydrocaffeic acid receptor (DCAR), DCAR-1. DCAR-1 is a novel seven-transmembrane protein that is expressed in the ASH avoidance sensory neurons of C. elegans. PMID:25086774 Dihydrocaffeic acid (DHCA) has been described as a potent ligand for DCAR-1 in both in vivo and in heterologous Xenopus oocyte assays |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000104 | ACCEPT | Summary: DCAR-1 initiates GPCR signalling: in the epidermis it acts upstream of (or in parallel to) the Galpha protein GPA-12 to control downstream p38 MAPK (PMK-1) signalling. Reason: Core biological process. Genetic epistasis places DCAR-1 at the top of a Galpha (GPA-12) -> p38 MAPK cascade, consistent with canonical GPCR signalling. Supporting Evidence: PMID:25086774 dcar-1 alone acts upstream or in parallel to GPA-12 |
| GO:0007165 signal transduction | IEA GO_REF:0000104 | KEEP AS NON CORE | Summary: Correct but generic. Signal transduction is a high-level parent of the more specific G protein-coupled receptor signaling pathway (GO:0007186) that is also annotated and better captures DCAR-1's activity. Reason: The term is not wrong - DCAR-1 does transduce signals - but it is subsumed by the more informative GPCR signaling pathway annotation, so it is retained as non-core rather than treated as a distinct core function. Supporting Evidence: PMID:25086774 multiple elements of the downstream signal transduction cascade |
| GO:0050832 defense response to fungus | IMP PMID:25086774 Activation of a G protein-coupled receptor by its endogenous... | ACCEPT | Summary: Loss of dcar-1 (RNAi and two null alleles, tm2484 and nj66) abolishes infection-induced antimicrobial peptide expression and markedly increases susceptibility to the fungus Drechmeria coniospora; DCAR-1 was the sole GPCR hit from a screen of 1,150 GPCR genes. Reason: Strong IMP evidence for a core function. DCAR-1 is required in the epidermis for the innate immune response to fungal infection. Supporting Evidence: PMID:25086774 dcar-1 emerged alone as an innate immune receptor gene acting upstream of (or in parallel to) gpa-12 PMID:25086774 dcar-1 mutants exhibited a markedly heightened susceptibility to D. coniospora infection |
| GO:0009611 response to wounding | IMP PMID:25086774 Activation of a G protein-coupled receptor by its endogenous... | ACCEPT | Summary: dcar-1 mutants show an almost complete block of antimicrobial peptide (nlp-29p::gfp) induction after sterile physical injury, showing that DCAR-1 mediates the response to wounding/damage independently of a pathogen - consistent with detection of an endogenous damage signal (HPLA/DAMP). Reason: Well-supported IMP for a core damage-sensing function; wounding and infection converge on the same DCAR-1-dependent, HPLA-driven pathway. Supporting Evidence: PMID:25086774 an almost complete block of nlp-29p::gfp induction following physical injury PMID:25086774 demonstrating that dcar-1 can be activated in the absence of a pathogen |
| GO:0016324 apical plasma membrane | IDA PMID:25086774 Activation of a G protein-coupled receptor by its endogenous... | ACCEPT | Summary: A rescuing dcar-1p::dcar-1::gfp translational reporter localized DCAR-1 to the apical surface of the major epidermal syncytium hyp7, the site where it acts to drive antimicrobial peptide expression. Reason: Direct IDA localization to the apical plasma membrane; a core cellular location for the receptor's immune function. Supporting Evidence: PMID:25086774 dcar-1 was expressed on the apical surface in the major epidermal syncytium, hyp7 |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane localization inferred from phylogeny is consistent with DCAR-1 being a cell-surface 7-TM GPCR and with the direct (IDA) apical plasma membrane localization in the epidermis. Reason: Correct and corroborated by experimental data; a parent of the more specific apical plasma membrane annotation. Supporting Evidence: PMID:25086774 dcar-1 was expressed on the apical surface in the major epidermal syncytium, hyp7 |
| GO:0016020 membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Generic membrane localization from InterPro/UniProt subcellular-location pipelines; correct for a multi-pass membrane protein but uninformative relative to the plasma membrane / apical plasma membrane annotations. Reason: Not wrong, but subsumed by the more specific and experimentally supported plasma membrane and apical plasma membrane terms. |
| GO:0097730 non-motile cilium | IDA PMID:22090488 A seven-transmembrane receptor that mediates avoidance respo... | KEEP AS NON CORE | Summary: WormBase IDA localization associated with DCAR-1's expression in the ciliated ASH (and ASI, PVQ) sensory neurons, where it detects the repellent DHCA. This reflects the neuronal chemosensory role, distinct from the epidermal immune role. Reason: The cached copy of PMID:22090488 is abstract-only, so the specific cilium sub-localization cannot be re-verified from the cached text; per curation policy the WormBase curator's experimental (IDA) call is trusted and not overruled. It is retained as a non-core location because it belongs to the neuronal chemosensory context rather than the flagship epidermal immune function. Supporting Evidence: PMID:22090488 expressed in the ASH avoidance sensory neurons of C. elegans |
| GO:0008188 neuropeptide receptor activity | IBA GO_REF:0000033 | REMOVE | Summary: This activity was propagated by phylogenetic (IBA) inference from the broad class A GPCR family (PTHR24243), some of whose members are neuropeptide receptors. However, the two experimentally characterized ligands of DCAR-1 are small-molecule catecholic/phenolic acids - HPLA (a tyrosine-derived metabolite/DAMP) in the epidermis and DHCA in neurons - not neuropeptides. Reason: Over-propagated family-level IBA that is contradicted by the direct experimental characterization of DCAR-1's ligands. DCAR-1 is not a neuropeptide receptor; its molecular function is adequately and correctly captured by G protein-coupled receptor activity (GO:0004930). Removing this avoids an unsupported and misleading molecular-function assertion. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN002797693 · PTHR24243 class A GPCR IBA seed node SUPPORTS SOURCE BUT NOT TARGET Neuropeptide-receptor activity is valid for genuine peptide-receptor members of this large class A GPCR family, but DCAR-1's characterized ligands are small-molecule metabolites (HPLA, DHCA), not neuropeptides. WB:WBGene00019616 · C. elegans family member in the IBA with/from set SUPPORTS SOURCE BUT NOT TARGET Co-annotated family member; it does not establish a neuropeptide ligand for DCAR-1. Supporting Evidence: PMID:25086774 the tyrosine derivative 4-hydroxyphenyllactic acid (HPLA) as an endogenous ligand PMID:25086774 Dihydrocaffeic acid (DHCA) has been described as a potent ligand for DCAR-1 in both in vivo and in heterologous Xenopus oocyte assays |
| GO:0007218 neuropeptide signaling pathway | IBA GO_REF:0000033 | REMOVE | Summary: Companion IBA propagation to the neuropeptide receptor activity call, inferred from the GPCR family rather than from DCAR-1's own biology. DCAR-1 signalling is driven by small-molecule ligands (HPLA, DHCA), not by neuropeptides. Reason: Over-propagated family-level IBA not supported by any evidence specific to DCAR-1 and contradicted by its characterized small-molecule ligands. The gene's signalling role is correctly captured by G protein-coupled receptor signaling pathway (GO:0007186) and the defense/wounding process terms. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN002797693 · PTHR24243 class A GPCR IBA seed node SUPPORTS SOURCE BUT NOT TARGET Neuropeptide signalling is valid for genuine peptide-receptor members of this family, but DCAR-1 signals in response to small-molecule metabolites (HPLA, DHCA), not neuropeptides. WB:WBGene00019616 · C. elegans family member in the IBA with/from set SUPPORTS SOURCE BUT NOT TARGET Co-annotated family member; it does not establish neuropeptide signalling for DCAR-1. Supporting Evidence: PMID:25086774 HPLA can act through DCAR-1 to regulate the epidermal innate immune response |
| GO:0007635 chemosensory behavior | IMP PMID:22090488 A seven-transmembrane receptor that mediates avoidance respo... | NEW | Summary: In ASH sensory neurons DCAR-1 is required for avoidance of the water- soluble repellent dihydrocaffeic acid (DHCA): dcar-1 null mutants are defective in DHCA avoidance and ASH-specific expression rescues the defect (Aoki et al. 2011), a role corroborated in Zugasti et al. 2014. Reason: Not present in GOA, but the neuronal chemosensory (repellent-avoidance) function is directly established by IMP evidence and is genetically separable from the epidermal immune role. Added so that the receptor's second, well-supported evolved function is captured in the structured annotations (mirrors the neuronal core_function). Supporting Evidence: PMID:22090488 dcar-1 mutant animals are defective in avoidance response to DHCA, and cell-specific expression of dcar-1 in the ASH neurons PMID:25086774 In neurons, dcar-1 mediates an avoidance response to specific repellents, acting in concert with ocr-2 and osm-9 |
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Download this section (compressed HTML)Q: Does DCAR-1 bind HPLA directly, and which extracellular/transmembrane residues form the ligand-binding pocket?
Suggested experts: Jonathan J Ewbank, Nathalie Pujol
Q: Do HPLA-sensing receptors functionally analogous to DCAR-1 exist outside the nematode phylum, given that HPLA is a conserved tyrosine metabolite?
Suggested experts: Jonathan J Ewbank
Experiment: Express DCAR-1 in a heterologous GPCR-activation system (as previously done with DHCA in Xenopus oocytes) and measure dose-dependent activation by HPLA and structurally related phenolic acids; test coupling specificity against GPA-12 versus other Galpha subunits.
Hypothesis: DCAR-1 is the direct receptor for HPLA and couples to GPA-12.
Type: heterologous receptor activation / ligand-response assay
Experiment: Use targeted metabolomics with isotope-labelled tyrosine to trace HPLA production before and after infection/wounding, combined with epidermis- specific RNAi/overexpression of candidate aminotransferases and reductases (e.g. tatn-1) to identify the biosynthetic enzymes.
Hypothesis: HPLA is generated in the epidermis by a defined tyrosine-catabolic route whose flux increases with damage.
Type: stable-isotope metabolomics + tissue-specific genetics
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The structural and biochemical basis of ligand recognition by DCAR-1 is unknown: there is no direct binding assay, no structure, and no defined ligand-binding pocket or residues. Whether DCAR-1 is the direct receptor for HPLA (versus an upstream/indirect sensor) has not been demonstrated biochemically.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: It is firmly established that DCAR-1 is a 7-TM class A GPCR required in the epidermis for HPLA/DHCA-triggered antimicrobial peptide induction and anti-fungal defense, and that it can respond to DHCA in a heterologous Xenopus oocyte system. The evidence that HPLA is the endogenous ligand is genetic and metabolomic (correlative), not a direct receptor-binding measurement.
Significance: HPLA is the first described damage-associated molecular pattern (DAMP) in C. elegans; defining how DCAR-1 binds it would establish the molecular logic of DAMP sensing by a metazoan GPCR and enable rational tests of whether analogous receptors exist beyond nematodes.
What would resolve it: Direct ligand-binding/activation assays (e.g. purified receptor or cell-based GPCR activation with HPLA titration), mutagenesis of predicted binding-pocket residues, and structural determination of the DCAR-1-HPLA complex.
Provenance (the field's own admissions):
Gap: It is unknown whether DCAR-1 has ligands or roles beyond HPLA/DHCA - including its natural neuronal ligand, whether it recognizes any microbe-associated molecular pattern, and whether it contributes to pathogen-avoidance behaviour as a second host-defense role.
OPEN BIOLOGY MF_DARK
What is known: DCAR-1 is known to detect the endogenous metabolite HPLA (epidermal immunity) and the exogenous repellent DHCA (neuronal avoidance via ASH/ASI/ PVQ with OCR-2/OSM-9). Beyond these, its ligand spectrum and the physiological relevance of its neuronal signalling to host defense are not established.
Significance: GPCRs are proposed to be an under-explored class of immunomodulatory receptors; clarifying whether DCAR-1 senses microbial patterns or only host damage signals would sharpen models of how nematodes discriminate infection from sterile injury.
What would resolve it: Systematic ligand/deorphanization screens, tests for direct microbe-derived agonists, and behavioural/immune assays separating DCAR-1's neuronal and epidermal contributions to defense.
Provenance (the field's own admissions):
Gap: The biosynthetic origin of the DAMP ligand HPLA, and the mechanism by which infection and cuticle damage raise its levels, are uncharacterized - including whether the invading fungus contributes to HPLA production or the increase is entirely host-derived.
OPEN BIOLOGY BP_DARK
What is known: HPLA is a tyrosine-derived metabolite that increases upon infection and in cuticle-defective dpy-10 mutants, and epidermal overexpression of the candidate aminotransferase tatn-1 raises dcar-1-dependent antimicrobial peptide expression. The enzymes and regulatory logic of HPLA production remain undefined and were only partially probed (candidate aminotransferase knockdowns were inconclusive, likely due to redundancy).
Significance: Understanding how HPLA is generated would reveal how damage and infection are converted into a diffusible immune-activating signal, and whether the pathway is a host stress response or a pathogen-influenced process.
What would resolve it: Genetic and biochemical dissection of tyrosine catabolism/HPLA synthesis in the epidermis, isotope-tracing of HPLA under infection, and host-versus- pathogen source discrimination.
Provenance (the field's own admissions):
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