Existing Annotations Review

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)

Core Functions

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:

G protein-coupled receptor activity

Directly Involved In:

innate immune response defense response to Gram-negative bacterium defense response to Gram-positive bacterium

Cellular Locations:

plasma membrane

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
FSHR-1 activates the expression of antimicrobial infection response genes in infected worms and delays accumulation of the ingested pathogen Pseudomonas aeruginosa

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:

G protein-coupled receptor activity

Directly Involved In:

response to oxidative stress stress response to cadmium ion

Cellular Locations:

plasma membrane

Supporting Evidence:

PMID:26360906
fshr-1(ok778) mutants died significantly more quickly than wild-type worms when exposed to paraquat
PMID:26360906
fshr-1(ok778) mutant worms fail to induce expression of gcs-1::gfp upon PA14 infection

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:19196974

The G protein-coupled receptor FSHR-1 is required for the Caenorhabditis elegans innate immune response

FSHR-1 identified in screen of LRR-containing transmembrane receptors for immune function

"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"
Required for defense against Gram-negative and Gram-positive pathogens

"FSHR-1 as an important component of the C. elegans immune response to Gram-negative and Gram-positive bacterial pathogens"
Acts in the intestine

"FSHR-1 acts in the C. elegans intestine, the primary site of exposure to ingested pathogens"
Signals parallel to p38 MAPK pathway

"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"
Regulates transcriptional induction of antimicrobial effectors

"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"
May act as pathogen receptor or general immune booster

"FSHR-1 may act generally to boost the nematode immune response, or it may function as a pathogen receptor"

PMID:26360906

The Conserved G-Protein Coupled Receptor FSHR-1 Regulates Protective Host Responses to Infection and Oxidative Stress

FSHR-1 delays pathogen accumulation in the intestine

"fshr-1(ok778) mutants have already accumulated a significantly greater amount of the fluorescent pathogen in their intestinal lumens (P<0.0001)"
Required for defense against diverse pathogens including PA14, S. aureus, E. faecalis

"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)"
Required for survival of oxidative stress (paraquat) and cadmium stress

"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)"
NOT required for thermal stress survival

"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"
Regulates expression of immune and stress response genes

"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"
Required for induction of gcs-1 oxidative stress response gene

"fshr-1(ok778) mutant worms fail to induce expression of gcs-1::gfp upon PA14 infection"
Mediates learned pathogen avoidance behavior

"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"
Acts in intestine for all characterized functions

"Expression of fshr-1 in the intestine is necessary and sufficient for its role in the response to infection by PA14"
Proposed to be indirect sensor of infection rather than direct pattern recognition receptor

"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"

file:worm/fshr-1/fshr-1-deep-research-falcon.md

Deep research report on fshr-1

Suggested Experiments

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

📚 Additional Documentation

Deep Research Falcon

(fshr-1-deep-research-falcon.md)

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organism: worm
gene_id: fshr-1
gene_symbol: fshr-1
uniprot_accession: L8EC40
protein_description: 'SubName: Full=G-protein coupled receptors family 1 profile
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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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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

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.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: L8EC40
Protein Description: SubName: Full=G-protein coupled receptors family 1 profile domain-containing protein {ECO:0000313|EMBL:CCQ25711.1};
Gene Information: 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
Key Domains: GPCR_Rhodpsn. (IPR000276); GPCR_Rhodpsn_7TM. (IPR017452); Gphrmn_rcpt_fam. (IPR002131); Leu-rich_rpt. (IPR001611); LRR_dom_sf. (IPR032675)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "fshr-1" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

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

Research Target:

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.

Output

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.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

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.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: L8EC40
Protein Description: SubName: Full=G-protein coupled receptors family 1 profile domain-containing protein {ECO:0000313|EMBL:CCQ25711.1};
Gene Information: 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
Key Domains: GPCR_Rhodpsn. (IPR000276); GPCR_Rhodpsn_7TM. (IPR017452); Gphrmn_rcpt_fam. (IPR002131); Leu-rich_rpt. (IPR001611); LRR_dom_sf. (IPR032675)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "fshr-1" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

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

Research Target:

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.

Citations

powell2009thegproteincoupled pages 2-3
powell2009thegproteincoupled pages 5-6
powell2009thegproteincoupled pages 3-4
powell2009thegproteincoupled pages 6-6
powell2009thegproteincoupled pages 1-2
powell2009thegproteincoupled pages 4-5
https://doi.org/10.1073/pnas.0813048106
https://doi.org/10.1073/pnas.0813048106,

📄 View Raw YAML

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 when exposed to paraquat
      - 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

fshr-1

Gene Description

Existing Annotations Review

Core Functions

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.

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.

References

Suggested Questions for Experts

Suggested Experiments

Tags

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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