tol-1 (C. elegans) review notes

Status of inputs

• Review originally done from UniProt, GOA and cached literature; Falcon deep research arrived
  later and was cross-checked (see the section at the end).
• UniProt Q9N5Z3 is an unreviewed TrEMBL entry (1221 aa): signal peptide 1-23, LRR ectodomain,
  single TM helix 997-1021, cytoplasmic TIR domain 1054-1178. PDB 8SUF covers the ectodomain (26-996)
  in complex work with LAT-1.

Identity

• TOL-1 is the sole Toll/TLR family receptor in C. elegans
  PMID:26279230.
• It is a cell-surface receptor with two LRR domains, a TM helix and a TIR domain
  PMID:40588662.
• Phylogenetically its TIR clusters with Drosophila Toll, Nv-TLR and human TLR4 TIRs
  PMID:29109290.
  It is structurally a multiple-cysteine-cluster Toll-type receptor, not a vertebrate PRR-type TLR;
  C. elegans lacks MyD88 and NF-kappaB PMID:23112184.

Development (strongest, most recent evidence)

• Pujol 2001: of tol-1, trf-1, pik-1, ikb-1 deletion mutants, only tol-1 is required for development
  PMID:11516642.
• Carmona-Rosas 2025: TOL-1 LRR binds the lectin domain of the adhesion GPCR LAT-1 (latrophilin);
  KD ~186-200 nM by SPR; crystal/cryo-EM structure
  PMID:40588662,
  PMID:40588662.
  Interface mutations (TOL-1 Q712A/Y713A/G714A/N715A) that do not affect surface display phenocopy
  the deletion allele: embryonic arrest, malformed embryos, reduced brood size
  PMID:40588662.
  Interactions mostly in trans (mutually exclusive expression).
  Note that in this complex the paper frames TOL-1 as the ligand of LAT-1; whether TOL-1 itself
  transduces a signal via its TIR domain upon LAT-1 binding is not shown.

Pathogen avoidance / BAG neuron development

• Pujol 2001: tol-1 mutants defective in avoidance of Serratia marcescens; tol-1, trf-1, pik-1,
  ikb-1 not important for resistance to several pathogens
  PMID:11516642,
  PMID:11516642.
• Brandt & Ringstad 2015: TOL-1 acts in BAG CO2-sensing neurons, cell-specifically required and
  rescued there, regulates BAG gene expression, and acts with trf-1 and pik-1, upstream of pmk-3
  (a p38), to promote BAG development and function; ikb-1 acts antagonistically
  PMID:26279230
  PMID:26279230,
  PMID:26279230.
  This is a developmental/permissive role enabling a behaviour, not acute microbe recognition
  PMID:26279230.
• 2024: TOL-1 signals in neurons via PMK-1 to limit foraging [PMID:39532199 abstract-only].

Immunity (contested)

• Tenor & Aballay 2008: tol-1(nr2033) killed by Salmonella enterica, pharyngeal invasion; required for
  ABF-2 and HSP-16.41 expression PMID:17975555.
  Abstract only in cache.
• Conflicts: Pujol 2001 (no role in resistance to several pathogens); Hydra paper calls immune role
  "controversial" (PMID:23112184). Kamaladevi 2016 (PMID:27338631, abstract-only) reports tol-1 mutant
  hypersusceptibility to K. pneumoniae after L. casei pretreatment - weak, single-lab.
  Sugawara & Sakamoto 2019 (PMID:31384522): tol-1 mutants show increased expression of innate immune
  genes on B. infantis, i.e. not a simple positive immune signalling role.

Curation decisions (summary)

• GO:0038023 signaling receptor activity (IBA): ACCEPT (TM receptor with TIR; genetics places it upstream of trf-1/pik-1/pmk-3 in BAG).
• GO:0007165 signal transduction (IEA): ACCEPT.
• GO:0007166 cell surface receptor signaling pathway (TAS): ACCEPT.
• GO:0009792 embryo development (IMP): ACCEPT - core, reinforced by 2025 LAT-1 work.
• GO:0006952 defense response (IMP, Pujol): MODIFY to GO:0002209 behavioral defense response (what was measured was avoidance behaviour; same paper found no role in resistance).
• GO:0050829 defense response to Gram-negative bacterium (IMP, Tenor): KEEP_AS_NON_CORE - single-study, pathogen-specific, contested.
• NEW: GO:0001664 G protein-coupled receptor binding (LAT-1 is an adhesion GPCR; direct binding, structure, in vivo interface mutants). Comparator: teneurins (other latrophilin partners) carry the parent GO:0005102 signaling receptor binding; GPCR ligands (NPY, POMC, Rspo1) carry GO:0001664, so GPCR binding on a latrophilin ligand is within convention.
• Not proposed: GO:0002224 TLR signaling pathway, GO:0038187 PRR activity - no evidence TOL-1 binds microbial molecules; ligand is LAT-1 (endogenous). GO:0008063 Toll signaling pathway is defined around "the receptor Toll"; raised as a question rather than asserted.

Deep-research cross-check (2026-09-30)

Compared tol-1-deep-research-falcon.md with the review.
- Agrees: sole C. elegans Toll-family receptor; LAT-1 binding by the C-LRR (KD 186 nM), interface
mutants phenocopy the null, trans interaction; BAG-neuron developmental role enabling Serratia
avoidance; immune role pathogen-specific (Salmonella) and not upstream of TIR-1/PMK-1; no MyD88 or
NF-kappaB in the worm.
- Correction made (verified in full text, PMID:26279230): IKB-1 is antagonistic, not a co-acting
pathway member - "deletion of ikb-1 ... suppressed the CO2 avoidance defect caused by loss of either
tol-1 or pmk-3 function". Also added the BAG axon defect: "we found that 30% of tol-1 mutant BAG cells
exhibited abnormal axonal commissures". Description, core function 2 wording/support and the
PMID:26279230 finding statement were updated.
- Adds, not acted on: report details from Tenor & Aballay 2008 (no susceptibility to E. faecalis,
S. pneumoniae etc.; Salmonella triggers no avoidance) - cached abstract only, cannot be verified; they
would reinforce, not change, the KEEP_AS_NON_CORE decision. Expression in nerve ring, pharynx, valve,
gonad and vulva (Carmona-Rosas 2025) - no location annotations proposed.
- No annotation actions changed.