TOL-1 is the only Toll/Toll-like receptor family member encoded in the Caenorhabditis elegans genome. It is a single-pass type I transmembrane cell-surface receptor with a signal peptide, an extracellular region of two leucine-rich-repeat (LRR) domains with cysteine-rich flanking modules, a single transmembrane helix and a cytoplasmic TIR domain; by TIR-domain phylogeny it groups with Drosophila Toll and other Toll-type receptors. Its best-supported role is in development: tol-1 deletion mutants show embryonic arrest with malformed embryos, larval lethality and reduced brood size, and the extracellular C-terminal LRR domain binds directly (KD about 0.2 micromolar) to the lectin domain of the adhesion G-protein-coupled receptor latrophilin LAT-1, mostly in trans between neighbouring cells; point mutations at this interface phenocopy the null allele. In the nervous system TOL-1 acts in the CO2-sensing BAG neurons, together with homologues of TRAF (TRF-1) and IRAK/Pelle (PIK-1) and upstream of the p38 MAPK PMK-3, to promote BAG neuron gene expression, axon morphology and chemosensory function; the IkappaB homologue IKB-1 acts antagonistically, as its deletion suppresses the tol-1 CO2-avoidance defect. Loss of this developmental function abolishes avoidance of pathogenic Serratia marcescens. Neuronal TOL-1 signalling through PMK-1 has also been linked to feeding behaviour. A direct role in antibacterial immunity is limited and contested: tol-1 mutants are not generally hypersusceptible to pathogens, but one study reports susceptibility to Salmonella enterica with pharyngeal invasion and reduced expression of pharyngeal defence genes. C. elegans lacks MyD88 and NF-kappaB, and no microbial ligand of TOL-1 has been identified.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006952 defense response | IMP PMID:11516642 A reverse genetic analysis of components of the Toll signali... | MODIFY | Summary: Pujol et al. (2001) made tol-1 deletion mutants and found them defective in avoidance of pathogenic Serratia marcescens, while tol-1, trf-1, pik-1 and ikb-1 mutants were not important for resistance to a panel of pathogens. The phenotype underlying this IMP is therefore a behavioural avoidance defect, not a failure of physiological defence. Brandt and Ringstad (2015) later showed this behaviour depends on TOL-1 acting in the CO2-sensing BAG neurons. Reason: The annotation is sound but the generic parent hides what was actually measured. The same paper that supports it states that tol-1 is not important for resistance to several pathogens, and the defect it describes is avoidance behaviour. GO:0002209 behavioral defense response ("a behavioral response seeking to protect an organism from a perceived external threat") captures the observed phenotype precisely. The experimental IMP is kept, only made more specific. Later work indicates TOL-1 acts developmentally in BAG neurons to enable this behaviour (PMID:26279230), so the annotation reflects a required upstream role rather than acute pathogen recognition; this is noted, not used to overrule the curator. Proposed replacements: behavioral defense response Supporting Evidence: PMID:11516642 The tol-1 mutants are defective in their avoidance of pathogenic S. marcescens, although other chemosensory behaviors are wild type. PMID:11516642 None of them are important for the resistance of C. elegans to a number of pathogens. PMID:26279230 for pathogen avoidance TOL-1 signaling is required in the chemosensory BAG neurons, where it regulates gene expression and is necessary for their chemosensory function |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping from the cytoplasmic TIR domain (IPR000157). TOL-1 is a transmembrane receptor with a TIR domain, and genetic epistasis places it upstream of TRAF, IRAK/Pelle and p38 MAPK homologues in BAG neurons. Reason: Broad but correct. The TIR domain is the signalling module of Toll-family receptors, and cell-specific genetics show TOL-1 acts with conserved Toll-pathway homologues to regulate gene expression in BAG neurons. More specific process terms are carried by the experimental rows. Supporting Evidence: PMID:26279230 Genetic studies revealed that TOL-1 acts together with many conserved components of TLR signaling. |
| GO:0007166 cell surface receptor signaling pathway | TAS PMID:11516642 A reverse genetic analysis of components of the Toll signali... | ACCEPT | Summary: Traceable author statement from Pujol et al. (2001), which analysed tol-1 as the receptor of a candidate nematode Toll pathway. TOL-1 is a cell-surface receptor (surface display confirmed in PMID:40588662) and acts upstream of trf-1, pik-1, ikb-1 and pmk-3 in BAG neurons (PMID:26279230). Reason: Appropriate level of specificity. TOL-1 is a single-pass cell-surface receptor with a cytoplasmic TIR domain, and later genetic work supports a TOL-1-initiated signalling pathway in neurons. The more specific GO:0008063 Toll signaling pathway is defined around the Drosophila receptor Toll and its ligand Spatzle; TOL-1 has no Spatzle homologue ligand identified, so the generic cell-surface-receptor term is preferred here. GO:0002224 toll-like receptor signaling pathway would be wrong, as its definition requires direct binding of microbial pattern motifs, which has not been shown for TOL-1. Supporting Evidence: PMID:11516642 We have generated and characterized deletion mutants for four genes supposed to function in a nematode Toll signaling pathway. PMID:40588662 We observed that the WT and quadruple mutant TOL-1 were displayed on the cell surface at very similar levels |
| GO:0009792 embryo development ending in birth or egg hatching | IMP PMID:11516642 A reverse genetic analysis of components of the Toll signali... | ACCEPT | Summary: tol-1 deletion mutants have developmental defects (Pujol et al. 2001). This was independently confirmed and extended by Carmona-Rosas et al. (2025): tol-1(nr2013) embryos arrest and appear malformed, and CRISPR point mutations that specifically break the TOL-1/LAT-1 interface without affecting surface display phenocopy the deletion. Reason: Experimental IMP, independently replicated, with a molecular mechanism: TOL-1 binds the latrophilin LAT-1, and the LAT-1-binding surface is needed for embryonic survival. This is the best-supported biological role of TOL-1 and is a core function. Supporting Evidence: PMID:11516642 Of these four genes, only tol-1 is required for nematode development. PMID:40588662 we independently confirmed that lat-1 and tol-1 are necessary for embryonic development, as a significant fraction of lat-1(ok1465) or tol-1(nr2013) homozygous embryos arrest and appear malformed at 20 Β°C PMID:40588662 Because simultaneous substitution of these four TOL-1 residues, which are critical for LAT-1 binding in vitro, phenocopy the effect of the tol-1 deletion allele in vivo, we propose that the LAT-1-binding surface of TOL-1 is essential |
| GO:0038023 signaling receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference from an ancestral node covering Toll/TLR and related LRR receptors. TOL-1 has the full receptor architecture (signal peptide, LRR ectodomain, TM helix, cytoplasmic TIR domain), is displayed at the cell surface, and acts cell-autonomously in BAG neurons upstream of downstream signalling components. Reason: The generic receptor activity is the correct level for TOL-1. It is inside the clade with Toll-type receptors and retains every domain required. No PRR activity or ligand-specific receptor term is implied, which is appropriate because no microbial ligand has been demonstrated. Whether LAT-1 binding triggers TIR-dependent signalling by TOL-1, or TOL-1 acts only as the ligand for LAT-1, is not yet resolved (see suggested questions); the BAG-neuron genetics are independent support that TOL-1 transduces a signal. Supporting Evidence: PMID:26279230 Importantly, loss of tol-1 function specifically in BAG cells recapitulated the pathogen avoidance defect of tol-1 mutants, and BAG cell-specific rescue of pmk-3 and tol-1 restored pathogen avoidance behavior to the corresponding mutants |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:17975555 A conserved Toll-like receptor is required for Caenorhabditi... | KEEP AS NON CORE | Summary: Tenor and Aballay (2008) report that tol-1(nr2033) mutants are killed by Salmonella enterica, which invades the pharynx, and that TOL-1 is needed for normal expression of the pharyngeal defensin-like ABF-2 and of HSP-16.41. Only the abstract is cached. Reason: Experimental IMP from a curator who had the full text; not overruled. It is kept as non-core because the immune role of TOL-1 is pathogen-specific and contested: the original deletion study found tol-1 not important for resistance to several pathogens (PMID:11516642), a later study found tol-1 mutants have elevated rather than reduced innate-immune gene expression on Bifidobacterium infantis (PMID:31384522), and C. elegans lacks MyD88 and NF-kappaB. The main defence pathway of the worm (TIR-1/NSY-1/SEK-1/PMK-1) is TOL-1-independent. Supporting Evidence: PMID:17975555 C. elegans tol-1(nr2033) mutants are killed by the human pathogen Salmonella enterica, which causes a significant pharyngeal invasion in the absence of TOL-1-mediated immunity PMID:23112184 a clear immune function of the TLR homolog TOL-1 is controversial and central components of vertebrate TLR signaling including the key adapter protein myeloid differentiation primary response gene 88 (MyD88) and the transcription factor NF-ΞΊB are not present PMID:31384522 A microarray analysis revealed that the expression of innate immune response-related genes was significantly increased in the tol-1 mutant. |
| GO:0001664 G protein-coupled receptor binding | IDA PMID:40588662 Structural basis and functional roles for Toll-like receptor... | NEW | Summary: The extracellular C-terminal LRR domain of TOL-1 binds directly to the lectin domain of the adhesion GPCR latrophilin LAT-1, shown by an extracellular interaction screen, SPR (KD about 186-200 nM), and crystal and cryo-EM structures of the complex. Interface point mutations that leave TOL-1 surface display intact abolish binding and phenocopy the tol-1 null in embryos. Reason: Not in GOA, and the evidence is direct, structural, quantitative and tested in vivo. The authors describe TOL-1 as a ligand for LAT-1, i.e. TOL-1 binds a GPCR. Comparator check: soluble and membrane ligands of GPCRs (e.g. NPY, POMC, R-spondin) carry GO:0001664; the other known latrophilin partners, the teneurins, carry the parent GO:0005102 signaling receptor binding. GO:0001664 is therefore within convention and more specific; GO:0005102 would be an acceptable fallback. This is a molecular function, not a process term, so the participation test does not arise. Supporting Evidence: PMID:40588662 The extracellular lectin domain of LAT-1 directly binds to the second leucine-rich repeat domain of TOL-1. PMID:40588662 We observed a dissociation constant (KD) of 186 nM for WT TOL-1 and LAT-1 PMID:40588662 LPHNs have large extracellular regions (ECRs) comprising a lectin, an olfactomedin, a hormone receptor (HormR) and a GPCR autoproteolysis-inducing (GAIN) domain |
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Download this section (compressed HTML)Q: Does LAT-1 binding activate TIR-dependent signalling by TOL-1, or does TOL-1 act only as the ligand that activates LAT-1 in the adjacent cell? The 2025 structure frames TOL-1 as the ligand, while the BAG-neuron genetics treat it as a signalling receptor; the two roles may be separate.
Q: Should the TOL-1 pathway in BAG neurons (TOL-1, TRF-1, PIK-1, IKB-1) be annotated to GO:0008063 Toll signaling pathway? Its definition names "the receptor Toll", no Spatzle-like ligand is known for TOL-1, and the output is p38 MAPK rather than NF-kappaB, so a curator decision on scope is needed rather than an automatic transfer.
Q: Is the reported requirement of TOL-1 for defence against Salmonella enterica (PMID:17975555) reproducible, and is it an indirect consequence of the developmental role of TOL-1 in the pharynx or nervous system?
Experiment: Express the TOL-1 TIR domain-deleted receptor, or a TIR loss-of-function point mutant, from the endogenous locus and test embryonic survival, BAG neuron marker expression and CO2 avoidance.
Hypothesis: If embryonic development needs only the LAT-1-binding ectodomain, a TIR mutant will be viable but defective in BAG function, separating the ligand role from the receptor role of TOL-1.
Type: CRISPR knock-in domain analysis
Experiment: Infect tol-1 null and LAT-1-interface point mutants, with BAG-specific and pharynx-specific rescue lines, with Salmonella enterica and score survival and pharyngeal colonisation.
Hypothesis: Salmonella susceptibility is secondary to developmental defects rather than a direct TOL-1-dependent immune signalling response.
Type: genetic infection assay
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Download this section (compressed HTML)tol-1 encodes a predicted transmembrane protein that is the sole C. elegans Toll-like receptor (TLR); TOL-1 is required for proper embryonic development and for pathogen avoidance behavior, and is expressed primarily in the nervous system.
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