FSHR-1 is a G protein-coupled receptor (GPCR) with leucine-rich repeats in its extracellular domain that functions in the C. elegans intestine as an essential component of the innate immune response. Unlike its mammalian FSHR ortholog which responds to follicle-stimulating hormone, FSHR-1 has been repurposed in C. elegans to detect and respond to infection and oxidative damage. FSHR-1 signals in parallel to the p38 MAPK pathway to activate transcription of antimicrobial effectors and oxidative stress response genes (including gcs-1). It is required for defense against diverse pathogens including Gram-negative bacteria (Pseudomonas aeruginosa), Gram-positive bacteria (Staphylococcus aureus, Enterococcus faecalis), and fungal pathogens (Candida albicans). FSHR-1 also mediates survival of oxidative stress (paraquat) and heavy metal stress (cadmium), but not thermal stress. Additionally, FSHR-1 is required for learned aversive behavior toward pathogens. The broad specificity of response suggests FSHR-1 acts as an indirect sensor of infection, possibly detecting host damage-associated molecular patterns rather than pathogen molecular patterns directly.
| 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.
Supporting Evidence:
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)
|
Q: What is the endogenous ligand for FSHR-1 in C. elegans? Does it bind a DAMP, pathogen-derived molecule, or host peptide?
Suggested experts: GPCR pharmacologists, C. elegans innate immunity researchers
Q: How does FSHR-1 signal to activate gene expression - what G protein subunits are involved?
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
provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2025-12-29T11:42:27.779612'
end_time: '2025-12-29T11:46:52.290307'
duration_seconds: 264.51
template_file: templates/gene_research_go_focused.md
template_variables:
organism: worm
gene_id: fshr-1
gene_symbol: fshr-1
uniprot_accession: L8EC40
protein_description: 'SubName: Full=G-protein coupled receptors family 1 profile
domain-containing protein {ECO:0000313|EMBL:CCQ25711.1};'
gene_info: Name=fshr-1 {ECO:0000313|EMBL:CCQ25711.1, ECO:0000313|WormBase:C50H2.1b};
ORFNames=C50H2.1 {ECO:0000313|WormBase:C50H2.1b}, CELE_C50H2.1 {ECO:0000313|EMBL:CCQ25711.1};
organism_full: Caenorhabditis elegans.
protein_family: Not specified in UniProt
protein_domains: GPCR_Rhodpsn. (IPR000276); GPCR_Rhodpsn_7TM. (IPR017452); Gphrmn_rcpt_fam.
(IPR002131); Leu-rich_rpt. (IPR001611); LRR_dom_sf. (IPR032675)
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citation_count: 8
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'fshr-1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene fshr-1 (gene ID: fshr-1, UniProt: L8EC40) in worm.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'fshr-1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene fshr-1 (gene ID: fshr-1, UniProt: L8EC40) in worm.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Research plan summary
We verified target identity and organism; searched and extracted primary evidence; synthesized function, pathways, localization, and phenotypes; summarized limitations in recent literature (2023–2024); and compiled a concise evidence table.
Comprehensive research report: C. elegans fshr-1 (C50H2.1; UniProt L8EC40)
1) Key concepts and definitions
- Gene/protein identity and family: fshr-1 (locus C50H2.1) encodes FSHR-1, a leucine-rich repeat (LRR)-containing, rhodopsin-like G protein-coupled receptor (GPCR). It is the sole LGR-type, LRR-containing GPCR in C. elegans identified in an RNAi-based screen of LRR receptors for pathogen susceptibility phenotypes (publication: Feb 2009; URL: https://doi.org/10.1073/pnas.0813048106) (powell2009thegproteincoupled pages 2-3, powell2009thegproteincoupled pages 1-2).
- Domain architecture and structural features: The extracellular domain contains approximately nine LRRs; the receptor has seven transmembrane helices (7TM) and a large C-terminal cytoplasmic tail, consistent with rhodopsin-like GPCRs (powell2009thegproteincoupled pages 2-3).
- Primary biological role: FSHR-1 is required for the innate immune response of C. elegans to multiple bacterial pathogens (Gram-negative Pseudomonas aeruginosa PA14 and Gram-positive Staphylococcus aureus and Enterococcus faecalis) (powell2009thegproteincoupled pages 3-4, powell2009thegproteincoupled pages 5-6).
2) Mechanistic function, pathways, and signaling context
- Pathway relationships: Genetic interaction studies indicate that FSHR-1 signals in parallel to the p38 MAPK pathway (PMK-1) and the insulin/IGF (DAF-2) pathway. Double mutants (e.g., pmk-1; fshr-1) exhibit additive or enhanced pathogen sensitivity, and sets of pathogen-response genes regulated by FSHR-1 and PMK-1 overlap but are not identical, arguing against a simple linear pathway (publication date: Feb 2009; https://doi.org/10.1073/pnas.0813048106) (powell2009thegproteincoupled pages 3-4, powell2009thegproteincoupled pages 1-2).
- Transcriptional responses: In fshr-1 loss-of-function, induction of multiple PA14-response genes is markedly reduced, with several targets showing ≥10-fold lower induction compared to wild type upon PA14 exposure, demonstrating a role in mounting inducible antimicrobial responses rather than maintaining basal expression (powell2009thegproteincoupled pages 3-4, powell2009thegproteincoupled pages 4-5).
- Ligand knowledge: No endogenous ligand has been defined. C. elegans lacks canonical vertebrate FSH subunits, leading to two broad hypotheses: FSHR-1 could be a noncanonical hormone receptor for an unknown worm ligand or a pattern-recognition receptor (PRR)-like sensor whose extracellular LRRs detect host- or microbe-derived cues (powell2009thegproteincoupled pages 4-5, powell2009thegproteincoupled pages 5-6).
3) Cellular and tissue localization
- Tissue expression and site of action: FSHR-1 is expressed in several somatic tissues, most strongly in the intestine and neurons. Functional assays demonstrate that its intestinal activity is necessary and sufficient for pathogen resistance: intestinal-specific RNAi phenocopies systemic knockdown; intestinal expression (ges-1 promoter) rescues the pathogen sensitivity of the fshr-1(ok778) deletion; neuronal expression provides only partial rescue (powell2009thegproteincoupled pages 4-5, powell2009thegproteincoupled pages 3-4).
- Subcellular localization: Precise apical/basolateral membrane localization in intestinal cells was not resolved in the primary study; consequently, whether FSHR-1 acts as an apical PRR interacting directly with luminal cues, or as a basolateral/systemic receptor responding to endogenous signals remains undetermined (powell2009thegproteincoupled pages 5-6).
4) Experimental phenotypes and evidence strength
- Loss-of-function allele and RNAi: The fshr-1(ok778) deletion removes most LRRs and all seven transmembrane regions, behaving as a genetic null. fshr-1(ok778) mutants show increased sensitivity to PA14, S. aureus, and E. faecalis in bacterial killing assays, without shortened lifespan on nonpathogenic E. coli OP50, indicating a specific defect in pathogen resistance rather than general debility (powell2009thegproteincoupled pages 2-3, powell2009thegproteincoupled pages 5-6, powell2009thegproteincoupled pages 6-6).
- Rescue and sufficiency: Transgenic rescue with a genomic fragment or an intestinal ges-1::fshr-1 construct restores pathogen resistance to wild-type levels; neuronal ric-19::fshr-1 expression confers only partial rescue, supporting a primary intestinal role (powell2009thegproteincoupled pages 6-6, powell2009thegproteincoupled pages 4-5).
- Pathway genetics: pmk-1; fshr-1 double mutants and combinations with upstream p38 components (tir-1, nsy-1) show additive/enhanced sensitivity, reinforcing that FSHR-1 does not lie upstream of PMK-1 but in a parallel pathway converging on antimicrobial gene regulation (powell2009thegproteincoupled pages 3-4, powell2009thegproteincoupled pages 6-6).
5) Recent developments and latest research (2023–2024 emphasis)
- Literature availability: Using the available tools, no additional peer-reviewed sources from 2023–2024 focusing specifically on C. elegans fshr-1 could be retrieved. The foundational Powell et al., 2009 PNAS study remains the primary, authoritative source defining FSHR-1’s role in innate immunity, intestinal site of action, and parallel signaling with PMK-1 and DAF-2 (powell2009thegproteincoupled pages 1-2, powell2009thegproteincoupled pages 3-4). We note this as a limitation and encourage checking WormBase/UniProt release notes and recent reviews for updates beyond the scope of the retrieved evidence.
6) Applications and real-world implementations
- Conceptual and methodological applications: FSHR-1 serves as a model to study LRR-containing GPCRs (LGRs) as potential PRR-like sensors in barrier tissues. The intestinally-acting, LRR-bearing GPCR paradigm illustrates how animals without canonical TLRs in key contexts can deploy alternative receptor families to detect and orchestrate defense, providing a framework for comparative immunology and for designing genetic screens for barrier defense GPCRs in other organisms (powell2009thegproteincoupled pages 1-2, powell2009thegproteincoupled pages 5-6).
7) Expert opinions and analysis from the primary source
- Interpretive conclusions by the authors: The authors propose that FSHR-1 promotes innate immune responses by enhancing inducible antimicrobial gene expression and that it may function either as a PRR-like sensor or a noncanonical hormone receptor; pathway genetics place it in parallel to PMK-1/p38 and DAF-2/insulin signaling (Feb 2009; https://doi.org/10.1073/pnas.0813048106) (powell2009thegproteincoupled pages 3-4, powell2009thegproteincoupled pages 5-6, powell2009thegproteincoupled pages 4-5).
8) Quantitative data and statistics
- Domain count: ~9 extracellular LRRs; 7 transmembrane helices (powell2009thegproteincoupled pages 2-3).
- Transcriptional effects: Multiple PA14-response genes show ≥10-fold reduced induction in fshr-1(ok778) compared to wild type following pathogen exposure (powell2009thegproteincoupled pages 3-4).
- Pathogen spectrum and phenotype: Increased susceptibility to P. aeruginosa PA14 (Gram-negative), S. aureus, and E. faecalis (Gram-positive) in survival assays; no reduced lifespan on E. coli OP50 under nonpathogenic conditions (powell2009thegproteincoupled pages 5-6, powell2009thegproteincoupled pages 2-3).
9) Open questions
- Endogenous ligand(s) remain unidentified; mechanistic placement relative to cell-surface vs systemic cues is unresolved. Subcellular localization in intestine and any neuron-to-intestine regulatory axis require further clarification (powell2009thegproteincoupled pages 5-6, powell2009thegproteincoupled pages 4-5).
Evidence table
| Study (citation) | Year | Genotypes/Tools | Pathogens/Assays | Tissue Requirement | Pathway Relationship | Molecular Features | Phenotypes | Notes |
|---|---:|---|---|---|---|---|---|---|
| Powell JR, Kim DH, Ausubel FM. Proc. Natl. Acad. Sci. USA. DOI: https://doi.org/10.1073/pnas.0813048106 (powell2009thegproteincoupled pages 1-2, powell2009thegproteincoupled pages 2-3, powell2009thegproteincoupled pages 3-4) | 2009 | fshr-1(ok778) deletion; systemic and tissue-specific RNAi (intestinal ges-1); rescue transgenes (endogenous genomic fragment, ges-1::fshr-1, ric-19::fshr-1) | Pseudomonas aeruginosa PA14, Staphylococcus aureus, Enterococcus faecalis; bacterial killing/survival assays; transcriptional induction of PA14-response genes | Intestinal expression required and sufficient for pathogen resistance; neuronal expression gives partial rescue | Signals in parallel to PMK-1/p38 MAPK and to DAF-2/insulin pathways (double mutants show additive/intermediate sensitivity) | LRR-containing GPCR (reported ~9 LRRs); rhodopsin-like 7TM topology; large C-terminal cytoplasmic tail | fshr-1(ok778) shows increased sensitivity to PA14, S. aureus, E. faecalis; many PA14-response genes induced ≥10-fold less in mutant | Ligand not identified; proposed as noncanonical hormone receptor or pattern-recognition receptor; ok778 removes most LRRs and all seven transmembrane domains (powell2009thegproteincoupled pages 6-6) |
Table: Compact summary of primary experimental evidence from Powell et al. 2009 on C. elegans fshr-1 (C50H2.1), showing tools, assays, tissue requirement, pathway relationships, molecular features, and key phenotypes; useful as a quick reference for functional annotation and citation.
Mandatory verification checklist
- Gene symbol and description alignment: fshr-1 encodes an LRR-containing GPCR (FSHR-1), consistent with UniProt L8EC40 and Powell et al. (powell2009thegproteincoupled pages 2-3).
- Organism: Caenorhabditis elegans (powell2009thegproteincoupled pages 1-2).
- Protein family/domains: LGR/LRR-containing rhodopsin-like 7TM GPCR with ~9 LRRs (powell2009thegproteincoupled pages 2-3).
- Ambiguity check: No conflicting gene symbol usage found within retrieved evidence; all data refer to C. elegans fshr-1/C50H2.1 (powell2009thegproteincoupled pages 1-2).
Primary citation with URL and date
- Powell JR, Kim DH, Ausubel FM. The G protein-coupled receptor FSHR-1 is required for the Caenorhabditis elegans innate immune response. Proceedings of the National Academy of Sciences of the USA. 2009 Feb;106(8):2782–2787. https://doi.org/10.1073/pnas.0813048106 (powell2009thegproteincoupled pages 1-2, powell2009thegproteincoupled pages 3-4, powell2009thegproteincoupled pages 2-3, powell2009thegproteincoupled pages 5-6, powell2009thegproteincoupled pages 4-5).
References
(powell2009thegproteincoupled pages 2-3): Jennifer R. Powell, Dennis H. Kim, and Frederick M. Ausubel. The g protein-coupled receptor fshr-1 is required for the caenorhabditis elegans innate immune response. Proceedings of the National Academy of Sciences, 106:2782-2787, Feb 2009. URL: https://doi.org/10.1073/pnas.0813048106, doi:10.1073/pnas.0813048106. This article has 168 citations and is from a highest quality peer-reviewed journal.
(powell2009thegproteincoupled pages 1-2): Jennifer R. Powell, Dennis H. Kim, and Frederick M. Ausubel. The g protein-coupled receptor fshr-1 is required for the caenorhabditis elegans innate immune response. Proceedings of the National Academy of Sciences, 106:2782-2787, Feb 2009. URL: https://doi.org/10.1073/pnas.0813048106, doi:10.1073/pnas.0813048106. This article has 168 citations and is from a highest quality peer-reviewed journal.
(powell2009thegproteincoupled pages 3-4): Jennifer R. Powell, Dennis H. Kim, and Frederick M. Ausubel. The g protein-coupled receptor fshr-1 is required for the caenorhabditis elegans innate immune response. Proceedings of the National Academy of Sciences, 106:2782-2787, Feb 2009. URL: https://doi.org/10.1073/pnas.0813048106, doi:10.1073/pnas.0813048106. This article has 168 citations and is from a highest quality peer-reviewed journal.
(powell2009thegproteincoupled pages 5-6): Jennifer R. Powell, Dennis H. Kim, and Frederick M. Ausubel. The g protein-coupled receptor fshr-1 is required for the caenorhabditis elegans innate immune response. Proceedings of the National Academy of Sciences, 106:2782-2787, Feb 2009. URL: https://doi.org/10.1073/pnas.0813048106, doi:10.1073/pnas.0813048106. This article has 168 citations and is from a highest quality peer-reviewed journal.
(powell2009thegproteincoupled pages 4-5): Jennifer R. Powell, Dennis H. Kim, and Frederick M. Ausubel. The g protein-coupled receptor fshr-1 is required for the caenorhabditis elegans innate immune response. Proceedings of the National Academy of Sciences, 106:2782-2787, Feb 2009. URL: https://doi.org/10.1073/pnas.0813048106, doi:10.1073/pnas.0813048106. This article has 168 citations and is from a highest quality peer-reviewed journal.
(powell2009thegproteincoupled pages 6-6): Jennifer R. Powell, Dennis H. Kim, and Frederick M. Ausubel. The g protein-coupled receptor fshr-1 is required for the caenorhabditis elegans innate immune response. Proceedings of the National Academy of Sciences, 106:2782-2787, Feb 2009. URL: https://doi.org/10.1073/pnas.0813048106, doi:10.1073/pnas.0813048106. This article has 168 citations and is from a highest quality peer-reviewed journal.
id: L8EC40
gene_symbol: fshr-1
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:6239
label: Caenorhabditis elegans
description: FSHR-1 is a G protein-coupled receptor (GPCR) with leucine-rich repeats
in its extracellular domain that functions in the C. elegans intestine as an essential
component of the innate immune response. Unlike its mammalian FSHR ortholog which
responds to follicle-stimulating hormone, FSHR-1 has been repurposed in C. elegans
to detect and respond to infection and oxidative damage. FSHR-1 signals in parallel
to the p38 MAPK pathway to activate transcription of antimicrobial effectors and
oxidative stress response genes (including gcs-1). It is required for defense against
diverse pathogens including Gram-negative bacteria (Pseudomonas aeruginosa), Gram-positive
bacteria (Staphylococcus aureus, Enterococcus faecalis), and fungal pathogens (Candida
albicans). FSHR-1 also mediates survival of oxidative stress (paraquat) and heavy
metal stress (cadmium), but not thermal stress. Additionally, FSHR-1 is required
for learned aversive behavior toward pathogens. The broad specificity of response
suggests FSHR-1 acts as an indirect sensor of infection, possibly detecting host
damage-associated molecular patterns rather than pathogen molecular patterns directly.
existing_annotations:
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:26360906
supporting_text: Expression of fshr-1 in the intestine is necessary and sufficient
for its role in the response to infection by PA14
- reference_id: file:worm/fshr-1/fshr-1-deep-research-falcon.md
supporting_text: 'model: Edison Scientific Literature'
- term:
id: GO:0007189
label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
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.
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: PMID:19196974
supporting_text: 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
- term:
id: GO:0009755
label: hormone-mediated signaling pathway
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
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.
action: REMOVE
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.
supported_by:
- reference_id: PMID:19196974
supporting_text: 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
- term:
id: GO:0008528
label: G protein-coupled peptide receptor activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
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.
action: MODIFY
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_replacement_terms:
- id: GO:0004930
label: G protein-coupled receptor activity
supported_by:
- reference_id: PMID:26360906
supporting_text: 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
- term:
id: GO:0004930
label: G protein-coupled receptor activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:19196974
supporting_text: We screened all LRR-containing transmembrane receptors in C.
elegans and identified the G protein-coupled receptor FSHR-1
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: IEA annotation based on UniProt subcellular location vocabulary mapping.
Consistent with FSHR-1 being a transmembrane GPCR.
action: ACCEPT
reason: Duplicate of the IBA annotation for plasma membrane. Both annotations
are valid and consistent with FSHR-1 being a transmembrane receptor.
- term:
id: GO:0007165
label: signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: IEA annotation based on UniProt keyword mapping. FSHR-1 participates
in signal transduction as a GPCR.
action: KEEP_AS_NON_CORE
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.
- term:
id: GO:0007186
label: G protein-coupled receptor signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: IEA annotation based on InterPro GPCR domain. FSHR-1 participates in
GPCR signaling in the intestine to regulate immune responses.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:19196974
supporting_text: the G protein-coupled receptor FSHR-1 as an important component
of the C. elegans immune response
- term:
id: GO:0016020
label: membrane
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: IEA annotation based on InterPro domain mapping. This is a more general
term than plasma membrane.
action: ACCEPT
reason: Correct but less specific than the plasma membrane annotation. FSHR-1
is a membrane protein with seven transmembrane domains.
- term:
id: GO:0016500
label: protein-hormone receptor activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: IEA annotation based on InterPro glycoprotein hormone receptor family
(IPR002131). This annotation implies FSHR-1 binds protein hormones.
action: REMOVE
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.
supported_by:
- reference_id: PMID:26360906
supporting_text: we propose that FSHR-1 is an indirect sensor of infection
- term:
id: GO:0050829
label: defense response to Gram-negative bacterium
evidence_type: IMP
original_reference_id: PMID:19196974
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:19196974
supporting_text: 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
- reference_id: PMID:26360906
supporting_text: 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)
- term:
id: GO:0006979
label: response to oxidative stress
evidence_type: IMP
original_reference_id: PMID:26360906
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:26360906
supporting_text: fshr-1(ok778) mutants died significantly more quickly than
wild-type worms (One-way ANOVA, F = 40.96; Tukey HSD test, P<0.01)
- reference_id: PMID:26360906
supporting_text: fshr-1(ok778) mutant worms fail to induce expression of gcs-1::gfp
upon PA14 infection
- term:
id: GO:0045087
label: innate immune response
evidence_type: IMP
original_reference_id: PMID:26360906
review:
summary: IMP annotation based on mutant phenotype. FSHR-1 is required for survival
of diverse pathogens and for transcriptional induction of antimicrobial effector
genes.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:19196974
supporting_text: 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
- reference_id: PMID:26360906
supporting_text: FSHR-1 activates the expression of antimicrobial infection
response genes in infected worms and delays accumulation of the ingested pathogen
Pseudomonas aeruginosa
- term:
id: GO:1990170
label: stress response to cadmium ion
evidence_type: IMP
original_reference_id: PMID:26360906
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:26360906
supporting_text: 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)
- reference_id: PMID:26360906
supporting_text: expression of fshr-1(+) from an intestinal promoter rescued
the cadmium sensitivity phenotype and conferred resistance to cadmium exposure
- term:
id: GO:0050830
label: defense response to Gram-positive bacterium
evidence_type: IMP
original_reference_id: PMID:19196974
review:
summary: NEW annotation based on experimental evidence. FSHR-1 is required for
defense against Gram-positive pathogens Staphylococcus aureus and Enterococcus
faecalis.
action: NEW
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.
supported_by:
- reference_id: PMID:19196974
supporting_text: 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
- reference_id: PMID:26360906
supporting_text: 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)
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
vocabulary mapping, accompanied by conservative changes to GO terms applied by
UniProt
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:19196974
title: The G protein-coupled receptor FSHR-1 is required for the Caenorhabditis
elegans innate immune response
findings:
- statement: FSHR-1 identified in screen of LRR-containing transmembrane receptors
for immune function
supporting_text: 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
- statement: Required for defense against Gram-negative and Gram-positive pathogens
supporting_text: FSHR-1 as an important component of the C. elegans immune response
to Gram-negative and Gram-positive bacterial pathogens
- statement: Acts in the intestine
supporting_text: FSHR-1 acts in the C. elegans intestine, the primary site of
exposure to ingested pathogens
- statement: Signals parallel to p38 MAPK pathway
supporting_text: 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
- statement: Regulates transcriptional induction of antimicrobial effectors
supporting_text: 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
- statement: May act as pathogen receptor or general immune booster
supporting_text: FSHR-1 may act generally to boost the nematode immune response,
or it may function as a pathogen receptor
- id: PMID:26360906
title: The Conserved G-Protein Coupled Receptor FSHR-1 Regulates Protective Host
Responses to Infection and Oxidative Stress
findings:
- statement: FSHR-1 delays pathogen accumulation in the intestine
supporting_text: fshr-1(ok778) mutants have already accumulated a significantly
greater amount of the fluorescent pathogen in their intestinal lumens (P<0.0001)
- statement: Required for defense against diverse pathogens including PA14, S. aureus,
E. faecalis
supporting_text: 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)
- statement: Required for survival of oxidative stress (paraquat) and cadmium stress
supporting_text: 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)
- statement: NOT required for thermal stress survival
supporting_text: "The mean survival of fshr-1(ok778) mutants at 37°C is not significantly\
\ different from the survival of wild-type worms (One-way ANOVA, F = 0.42, P\
\ = 0.669), indicating that the fshr-1 pathway does not respond to the damage\
\ caused by high heat"
- statement: Regulates expression of immune and stress response genes
supporting_text: when we examined the reported functions of the genes whose expression
in infected worms depends on fshr-1, we observed that many were known antimicrobial
infection response genes; in addition, 18% of fshr-1-regulated genes were associated
with some type of cellular stress
- statement: Required for induction of gcs-1 oxidative stress response gene
supporting_text: fshr-1(ok778) mutant worms fail to induce expression of gcs-1::gfp
upon PA14 infection
- statement: Mediates learned pathogen avoidance behavior
supporting_text: fshr-1(ok778) mutants are impaired in their ability to learn
pathogen avoidance. 45% of fshr-1(ok778) mutants remain on a lawn of PA14 after
9 hours of exposure
- statement: Acts in intestine for all characterized functions
supporting_text: Expression of fshr-1 in the intestine is necessary and sufficient
for its role in the response to infection by PA14
- statement: Proposed to be indirect sensor of infection rather than direct pattern
recognition receptor
supporting_text: 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
- id: file:worm/fshr-1/fshr-1-deep-research-falcon.md
title: Deep research report on fshr-1
findings: []
core_functions:
- description: FSHR-1 functions as a G protein-coupled receptor in the intestinal
epithelium to sense infection or infection-associated damage and activate innate
immune responses against diverse bacterial pathogens.
molecular_function:
id: GO:0004930
label: G protein-coupled receptor activity
directly_involved_in:
- id: GO:0045087
label: innate immune response
- id: GO:0050829
label: defense response to Gram-negative bacterium
- id: GO:0050830
label: defense response to Gram-positive bacterium
locations:
- id: GO:0005886
label: plasma membrane
supported_by:
- reference_id: PMID:19196974
supporting_text: 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
- reference_id: PMID:26360906
supporting_text: FSHR-1 activates the expression of antimicrobial infection response
genes in infected worms and delays accumulation of the ingested pathogen Pseudomonas
aeruginosa
- description: FSHR-1 regulates the oxidative stress response through activation of
detoxification genes including gcs-1, protecting the host from ROS damage during
infection and from exogenous oxidative stressors.
molecular_function:
id: GO:0004930
label: G protein-coupled receptor activity
directly_involved_in:
- id: GO:0006979
label: response to oxidative stress
- id: GO:1990170
label: stress response to cadmium ion
locations:
- id: GO:0005886
label: plasma membrane
supported_by:
- reference_id: PMID:26360906
supporting_text: fshr-1(ok778) mutants died significantly more quickly than wild-type
worms (One-way ANOVA, F = 40.96; Tukey HSD test, P<0.01) (Fig 2C and 2D)
- reference_id: PMID:26360906
supporting_text: fshr-1(ok778) mutant worms fail to induce expression of gcs-1::gfp
upon PA14 infection
suggested_questions:
- question: What is the endogenous ligand for FSHR-1 in C. elegans? Does it bind a
DAMP, pathogen-derived molecule, or host peptide?
experts:
- GPCR pharmacologists
- C. elegans innate immunity researchers
- question: How does FSHR-1 signal to activate gene expression - what G protein subunits
are involved?
experts:
- GPCR signaling specialists
- C. elegans signaling researchers
- question: What is the relationship between FSHR-1 and the p38 MAPK/pmk-1 pathway
at the molecular level?
experts:
- C. elegans immunity researchers
- MAPK signaling specialists
- question: Does FSHR-1 have any function in reproduction or development given its
sequence similarity to mammalian FSH receptor?
experts:
- C. elegans developmental biologists
- Reproductive biology specialists
suggested_experiments:
- experiment_type: Biochemical ligand identification
description: 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
- experiment_type: G protein coupling analysis
description: 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
- experiment_type: ROS sensing analysis
description: 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
- experiment_type: Tissue-specific RNAi
description: 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
proposed_new_terms: []
tags:
- caeel-surveillance-immunity