FSHR-1 is a leucine-rich-repeat G protein-coupled receptor and the sole C. elegans ortholog of the mammalian glycoprotein hormone receptors (FSHR, LHCGR, TSHR). The glycoprotein hormone subunit orthologs GPLA-1/GPA2 and GPLB-1/GPB5 activate it in vitro and act genetically upstream of it. FSHR-1 acts mainly in the intestine, where it is required for innate immunity. It signals in parallel to the p38 MAPK pathway to induce antimicrobial effectors and oxidative stress response genes (including gcs-1), and it is needed to resist Gram-negative (Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus, Enterococcus faecalis) bacteria, oxidative stress and cadmium, but not heat. Intestinal FSHR-1 also promotes acetylcholine release at neuromuscular junctions through inter-tissue signaling. fshr-1 mutants are resistant to aldicarb and accumulate synaptic vesicles and UNC-10/RIM in cholinergic motor neurons, and intestinal re-expression restores neuromuscular function. In this role GSA-1/Gas, ACY-1/adenylyl cyclase and SPHK-1 sphingosine kinase act genetically downstream of the receptor. FSHR-1 is also required for learned aversion to pathogens.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: FSHR-1 is a multi-pass transmembrane G protein-coupled receptor localized to the plasma membrane. UniProt annotations indicate Cell membrane localization. The IBA annotation is based on phylogenetic inference from mammalian FSHR orthologs which are established plasma membrane receptors. Reason: The plasma membrane localization is consistent with FSHR-1 being a GPCR that functions in intestinal cells to sense and respond to pathogens and stress. Intestinal expression of fshr-1 rescues the pathogen sensitivity phenotype (PMID:26360906). The seven transmembrane domains predicted in UniProt support plasma membrane localization. Supporting Evidence: PMID:26360906 Expression of fshr-1 in the intestine is necessary and sufficient for its role in the response to infection by PA14 file:worm/fshr-1/fshr-1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The IBA annotation infers adenylate cyclase-activating GPCR signaling based on phylogenetic relationships with mammalian glycoprotein hormone receptors (FSHR, TSHR, LHCGR) which canonically couple to Gs and activate adenylate cyclase. While FSHR-1 is structurally related to these receptors, direct evidence for cAMP/adenylate cyclase activation in C. elegans FSHR-1 signaling is limited. Reason: The annotation is phylogenetically reasonable based on FSHR-1 belonging to the glycoprotein hormone receptor family. However, the core function of FSHR-1 in C. elegans appears to be immune signaling rather than hormone response. The downstream signaling mechanism in C. elegans has not been fully characterized, and FSHR-1 signals in parallel to p38 MAPK pathway (PMID:19196974). Keep as non-core since the precise signaling mechanism in worms may differ from mammals. Later genetic evidence strengthens the claim for the neuromuscular role. Gain-of-function gsa-1/Gas and acy-1/adenylyl cyclase alleles suppress fshr-1 mutant phenotypes (PMID:39561202), consistent with the Gs coupling the IBA asserts. This is epistasis, not a biochemical cAMP assay, so the row stays non-core. Supporting Evidence: PMID:39561202 Epistasis experiments support a model in which GΞ±S and adenylyl cyclase, as well as SPHK signaling, act downstream of FSHR-1 in its control of neuromuscular activity PMID:19196974 FSHR-1 signals in parallel to the known p38 MAPK pathway but converges to regulate the transcriptional induction of an overlapping but nonidentical set of antimicrobial effectors |
| GO:0009755 hormone-mediated signaling pathway | IBA GO_REF:0000033 | REMOVE | Summary: This IBA annotation is based on phylogenetic inference from mammalian FSH receptor, which mediates follicle-stimulating hormone signaling. However, there is no evidence that FSHR-1 functions in hormone signaling in C. elegans. Reason: While FSHR-1 is structurally related to mammalian hormone receptors, its characterized function in C. elegans is in innate immunity and stress response, not hormone signaling. C. elegans lacks the gonadotropin hormones (FSH, LH, TSH) present in vertebrates. The publications (PMID:19196974, PMID:26360906) characterize FSHR-1 exclusively as an immune/stress response regulator. This annotation represents phylogenetic over-extension of function that does not apply to C. elegans. Supporting Evidence: PMID:19196974 We screened all LRR-containing transmembrane receptors in C. elegans and identified the G protein-coupled receptor FSHR-1 as an important component of the C. elegans immune response to Gram-negative and Gram-positive bacterial pathogens |
| GO:0008528 G protein-coupled peptide receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: The IBA annotation infers peptide receptor activity based on phylogenetic relationship with glycoprotein hormone receptors. The ligand for FSHR-1 in C. elegans has not been identified. Reason: FSHR-1 is a GPCR but its ligand in C. elegans is unknown. The term "G protein-coupled peptide receptor activity" implies binding to a peptide ligand, which is unconfirmed. Given that FSHR-1 may detect damage-associated molecular patterns or other infection-related signals rather than peptide hormones, the more general term "G protein-coupled receptor activity" is more appropriate. The ligand could be a DAMP or stress signal rather than a peptide. Proposed replacements: G protein-coupled receptor activity Supporting Evidence: PMID:26360906 Rather than serving as a direct PRR like fellow LRR-containing TLRs and NLRs, we propose that FSHR-1 is an indirect sensor of infection |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation based on InterPro GPCR domain and UniProt keywords. FSHR-1 contains the canonical GPCR 7TM domain and belongs to the rhodopsin-like GPCR family. Reason: FSHR-1 is unambiguously a GPCR based on sequence features (7TM domain, InterPro:IPR000276) and functional studies showing it signals to regulate gene expression in response to infection. This is the appropriate molecular function term for this receptor. Supporting Evidence: PMID:19196974 We screened all LRR-containing transmembrane receptors in C. elegans and identified the G protein-coupled receptor FSHR-1 |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProt subcellular location vocabulary mapping. Consistent with FSHR-1 being a transmembrane GPCR. Reason: Duplicate of the IBA annotation for plasma membrane. Both annotations are valid and consistent with FSHR-1 being a transmembrane receptor. |
| GO:0007165 signal transduction | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: IEA annotation based on UniProt keyword mapping. FSHR-1 participates in signal transduction as a GPCR. Reason: This is a high-level term that is correct but less informative than the more specific GPCR signaling annotations. FSHR-1 clearly functions in signal transduction to regulate immune and stress responses. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation based on InterPro GPCR domain. FSHR-1 participates in GPCR signaling in the intestine to regulate immune responses. Reason: FSHR-1 is a GPCR that signals to regulate transcription of antimicrobial and stress response genes. This annotation correctly describes its participation in GPCR signaling. Supporting Evidence: PMID:19196974 the G protein-coupled receptor FSHR-1 as an important component of the C. elegans immune response |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation based on InterPro domain mapping. This is a more general term than plasma membrane. Reason: Correct but less specific than the plasma membrane annotation. FSHR-1 is a membrane protein with seven transmembrane domains. |
| GO:0016500 protein-hormone receptor activity | IEA GO_REF:0000002 | REMOVE | Summary: IEA annotation based on InterPro glycoprotein hormone receptor family (IPR002131). This annotation implies FSHR-1 binds protein hormones. Reason: There is no evidence that FSHR-1 functions as a hormone receptor in C. elegans. The ligand is unknown but appears to be related to infection/damage sensing rather than hormone signaling. C. elegans lacks vertebrate gonadotropins. The InterPro domain match reflects sequence similarity rather than functional conservation. Supporting Evidence: PMID:26360906 we propose that FSHR-1 is an indirect sensor of infection |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:19196974 The G protein-coupled receptor FSHR-1 is required for the Ca... | ACCEPT | Summary: IMP annotation based on mutant phenotype. fshr-1 mutants are hypersensitive to killing by Pseudomonas aeruginosa PA14 (Gram-negative pathogen). FSHR-1 activates antimicrobial gene expression in response to PA14 infection. Reason: Core function of FSHR-1. The original characterization paper (PMID:19196974) identified FSHR-1 in a screen for immune regulators and demonstrated its requirement for defense against Gram-negative PA14. This is strongly supported by experimental evidence including survival assays, gene expression studies, and rescue experiments. Supporting Evidence: PMID:19196974 We screened all LRR-containing transmembrane receptors in C. elegans and identified the G protein-coupled receptor FSHR-1 as an important component of the C. elegans immune response to Gram-negative and Gram-positive bacterial pathogens PMID:26360906 infected fshr-1(ok778) worms have a mean survival time of 39 hours, significantly less than the wild-type mean survival time of 73 hours (P<0.0001) |
| GO:0006979 response to oxidative stress | IMP PMID:26360906 The Conserved G-Protein Coupled Receptor FSHR-1 Regulates Pr... | ACCEPT | Summary: IMP annotation based on mutant phenotype. fshr-1 mutants are hypersensitive to paraquat-induced oxidative stress. FSHR-1 is required for induction of the oxidative stress response gene gcs-1 upon infection. Reason: Core function of FSHR-1. The study showed fshr-1(ok778) mutants died significantly faster than wild-type when exposed to paraquat. FSHR-1 is required for gcs-1::gfp induction upon PA14 infection. Intestinal expression of fshr-1 rescues the paraquat sensitivity phenotype. Supporting Evidence: PMID:26360906 fshr-1(ok778) mutants died significantly more quickly than wild-type worms (One-way ANOVA, F = 40.96; Tukey HSD test, P<0.01) PMID:26360906 fshr-1(ok778) mutant worms fail to induce expression of gcs-1::gfp upon PA14 infection |
| GO:0045087 innate immune response | IMP PMID:26360906 The Conserved G-Protein Coupled Receptor FSHR-1 Regulates Pr... | ACCEPT | Summary: IMP annotation based on mutant phenotype. FSHR-1 is required for survival of diverse pathogens and for transcriptional induction of antimicrobial effector genes. Reason: Core function of FSHR-1. Extensive evidence supports FSHR-1 as an essential component of C. elegans innate immunity. It regulates antimicrobial gene expression, delays pathogen accumulation in the intestine, and mediates pathogen avoidance behavior. Functions against Gram-negative, Gram-positive, and fungal pathogens. Supporting Evidence: PMID:19196974 the G protein-coupled receptor FSHR-1 as an important component of the C. elegans immune response to Gram-negative and Gram-positive bacterial pathogens PMID:26360906 FSHR-1 activates the expression of antimicrobial infection response genes in infected worms and delays accumulation of the ingested pathogen Pseudomonas aeruginosa |
| GO:1990170 stress response to cadmium ion | IMP PMID:26360906 The Conserved G-Protein Coupled Receptor FSHR-1 Regulates Pr... | ACCEPT | Summary: IMP annotation based on mutant phenotype. fshr-1 mutants are hypersensitive to cadmium stress. Intestinal expression of fshr-1 rescues the cadmium sensitivity phenotype. Reason: Well-supported experimental annotation. The study demonstrated fshr-1 is required for survival of cadmium stress, and this is likely related to the oxidative stress response pathway since cadmium induces ROS production. Supporting Evidence: PMID:26360906 fshr-1(ok778) mutants died significantly more quickly in the presence of cadmium than wild-type worms (One-way ANOVA, F = 110.68; Tukey HSD test, P<0.05) PMID:26360906 expression of fshr-1(+) from an intestinal promoter rescued the cadmium sensitivity phenotype and conferred resistance to cadmium exposure |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:19196974 The G protein-coupled receptor FSHR-1 is required for the Ca... | NEW | Summary: NEW annotation based on experimental evidence. FSHR-1 is required for defense against Gram-positive pathogens Staphylococcus aureus and Enterococcus faecalis. Reason: The publications demonstrate fshr-1 mutants are sensitive to Gram-positive pathogens S. aureus and E. faecalis, not just Gram-negative PA14. This is explicitly stated in both publications. The annotation for Gram-negative defense exists but the corresponding Gram-positive annotation should be added. Supporting Evidence: PMID:19196974 the G protein-coupled receptor FSHR-1 as an important component of the C. elegans immune response to Gram-negative and Gram-positive bacterial pathogens PMID:26360906 fshr-1(ok778) mutants are more sensitive than wild-type worms to infection by diverse pathogens, including not only the Gram negative pathogen PA14, but also the Gram positive bacterial pathogens Staphylococcus aureus (P>0.01) and Enterococcus faecalis (P>0.05) |
| GO:1900075 positive regulation of neuromuscular synaptic transmission | IMP PMID:39561202 Cell non-autonomous signaling through the conserved C. elega... | NEW | Summary: NEW annotation. FSHR-1 promotes cholinergic transmission at the neuromuscular junction. Loss of fshr-1 causes aldicarb resistance, reduced muscle contraction and synaptic vesicle accumulation in cholinergic motor neurons. Intestinal re-expression rescues these defects, and intestine-specific knockdown reproduces them. Reason: The WormBase curated description (file:worm/fshr-1/fshr-1-deep-research-wormbase.md) pointed to this role, which the review had missed. A dedicated study (PMID:39561202) confirms it, building on the original RNAi screen hit (PMID:16049479). A regulation term is the right shape. FSHR-1 is a receptor whose signaling, mainly from the intestine, increases synaptic vesicle release. It does not carry out synaptic transmission itself, so a participation term such as chemical synaptic transmission would be wrong. The effect is cell non-autonomous, and the relay from intestine to motor neuron is not identified. The term is therefore non-core context and not part of core_functions. It is preferred to GO:0032224 (positive regulation of synaptic transmission, cholinergic) because the synapse is neuromuscular. Supporting Evidence: PMID:39561202 Inhibition of fshr-1 expression reduces muscle contraction and leads to synaptic vesicle accumulation in cholinergic motor neurons. PMID:39561202 Intestine-specific knockdown of FSHR-1 reduces neuromuscular function, indicating FSHR-1 is both necessary and sufficient in the intestine for its neuromuscular effects. |
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Download this section (compressed HTML)Q: GPLA-1/GPA2 and GPLB-1/GPB5 activate FSHR-1 in vitro and act upstream of it at the neuromuscular junction (PMID:39561202). Are they also the ligands in the immune response, or does infection activate FSHR-1 through a different, damage-associated signal?
Suggested experts: GPCR pharmacologists, C. elegans innate immunity researchers
Q: For the neuromuscular role, GSA-1/Gas and ACY-1 act genetically downstream (PMID:39561202). Does the intestinal immune response use the same Gs-cAMP route, and what intestinal signal relays FSHR-1 activity to cholinergic motor neurons?
Suggested experts: GPCR signaling specialists, C. elegans signaling researchers
Q: What is the relationship between FSHR-1 and the p38 MAPK/pmk-1 pathway at the molecular level?
Suggested experts: C. elegans immunity researchers, MAPK signaling specialists
Q: Does FSHR-1 have any function in reproduction or development given its sequence similarity to mammalian FSH receptor?
Suggested experts: C. elegans developmental biologists, Reproductive biology specialists
Experiment: Identify FSHR-1 ligand through biochemical purification or receptor-ligand screens using infected worm extracts or pathogen-conditioned media
Hypothesis: FSHR-1 binds a damage-associated molecular pattern or host stress signal rather than a peptide hormone
Type: Biochemical ligand identification
Experiment: Determine G protein coupling specificity using mutant analysis of Gs, Gq, and other G protein subunits in combination with fshr-1
Hypothesis: FSHR-1 couples to specific G protein subunits to activate immune gene expression
Type: G protein coupling analysis
Experiment: Investigate potential role of FSHR-1 in detecting reactive oxygen species or lipid peroxidation products as DAMPs
Hypothesis: FSHR-1 senses oxidative damage caused by infection rather than pathogen molecules directly
Type: ROS sensing analysis
Experiment: Test whether FSHR-1 functions in other tissues besides intestine using tissue-specific RNAi or rescue
Hypothesis: FSHR-1 function is restricted to the intestine where it encounters ingested pathogens
Type: Tissue-specific RNAi
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