TOLL9 (AGAP006974) is an Anopheles gambiae Toll-family membrane receptor with extracellular leucine-rich repeats and an intracellular TIR domain. Its conserved receptor architecture and phylogenetic placement support transmembrane signaling, while immune-family homology and altered expression in immune-activated mosquitoes suggest an innate-defense role. The physiological ligand, accessory proteins and downstream pathway of this particular mosquito receptor remain incompletely established. Related insect Toll9 proteins can recognize lipopolysaccharide through MD-2-like partners, so ligand recognition need not follow the Spaetzle mechanism of canonical Drosophila Toll.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006954 inflammatory response | IBA GO_REF:0000033 | REMOVE | Summary: The exact GO term has an explicit vertebrate-only taxon constraint. Reason: QuickGO GO:0006954 complete response specifies only_in_taxon Vertebrata (7742), which excludes Anopheles. The frozen annotation propagated from ancestral PTN000687652; current IBD instead places this term on PTN002808115 outside the target lineage, and current QuickGO no longer returns the row. Preserve the source row and retain REMOVE for this concrete taxonomic incompatibility. Lack of adaptive immunity is not the rationale, and insect innate defense remains biologically valid. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH Sources checked: PANTHER:PTN000687652 SUPPORTS SOURCE BUT NOT TARGET Frozen 2025 GOA propagated from this target ancestor, but the exact term is restricted to vertebrates. Current IBD places the term at off-lineage PTN002808115 and current QuickGO omits the mosquito assertion; source-version differences do not establish why the earlier placement changed. Supporting Evidence: file:ANOGA/TOLL9/TOLL9-notes.md QuickGO explicitly restricts GO:0006954 to Vertebrata (NCBITaxon:7742). |
| GO:0007165 signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: The receptor and TIR domain support signal transduction. Reason: The target leaf descends from the current positive PTN002808045 for this term, and the TIR-domain mapping independently agrees. The previous specific replacement presumed an AGAP006974 Spaetzle–Myd88–Tube–Pelle mechanism from other receptors and pathway-wide experiments. Retain the supported broad assertion while ligand and pathway specificity are adjudicated. Supporting Evidence: UniProt:Q5TWL7 Belongs to the Toll-like receptor family. |
| GO:0038023 signaling receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Conserved Toll-receptor architecture and ancestral placement support signaling receptor activity. Reason: Current PTN002808045 supports this target. The previous replacement with pattern recognition receptor activity was justified by processed host Spaetzle, which is not a microbial PAMP. Bombyx Toll9 has genuine LPS/MD-2-like recognition evidence, so PRR capacity is a serious separate hypothesis; it is not established for this receptor by the prior rationale. Supporting Evidence: UniProt:Q5TWL7 Belongs to the Toll-like receptor family. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The conserved Toll membrane-receptor topology supports plasma-membrane signaling. Reason: Retain the ancestral plasma-membrane annotation from PTN002808045. The LRR–membrane–TIR architecture is consistent, and no target-specific loss or alternative exclusive localization has been established. The UniProt prediction also includes a hydrophobic N-terminal segment; it is not an experimental map of mature topology. Supporting Evidence: UniProt:Q5TWL7 Belongs to the Toll-like receptor family. |
| GO:0002376 immune system process | IEA GO_REF:0000043 | ACCEPT | Summary: An immune role remains a reasonable conserved Toll9-family inference. Reason: The existing keyword inference is supported by Toll9 immune activity in Bombyx and immune-associated target expression in PMID:38191283. That study perturbs mosGILT rather than TOLL9 and does not itself prove receptor-specific antiparasite work. Drosophila Toll9 knockout results are context-specific and do not establish loss in Anopheles. Supporting Evidence: UniProt:Q5TWL7 Belongs to the Toll-like receptor family. PMID:38191283 (AGAP006974, fold change 2, p-value 0.0095) PMID:33963082 experiments showed that BmToll9 from the silkmoth Bombyx mori also recognized LPS through interaction with two MD-2-like proteins, |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: The receptor and TIR domain support signal transduction. Reason: The target leaf descends from the current positive PTN002808045 for this term, and the TIR-domain mapping independently agrees. The previous specific replacement presumed an AGAP006974 Spaetzle–Myd88–Tube–Pelle mechanism from other receptors and pathway-wide experiments. Retain the supported broad assertion while ligand and pathway specificity are adjudicated. Supporting Evidence: UniProt:Q5TWL7 Belongs to the Toll-like receptor family. |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The protein contains a conserved hydrophobic receptor membrane segment. Reason: The broad membrane annotation is true and independently supported by the deposited sequence and subcellular-location mapping. Coexistence with plasma membrane does not make an existing broad annotation an over-annotation. Supporting Evidence: UniProt:Q5TWL7 Belongs to the Toll-like receptor family. |
| GO:0045087 innate immune response | IEA GO_REF:0000043 | ACCEPT | Summary: Innate immunity is a plausible conserved Toll9-family role, with target-specific mechanism still unresolved. Reason: Retain the existing family-based keyword inference. Bombyx Toll9 has positive LPS-responsive immune signaling, while target AGAP006974 is upregulated in mosGILT-null mosquitoes. These are not direct Anopheles TOLL9 ligand or loss-of-function assays. Drosophila Toll9 loss-of-function lacks defects in tested antibacterial responses but does not refute every ancestral or mosquito immune role; a focused report will assess the transfer scope. Supporting Evidence: UniProt:Q5TWL7 Belongs to the Toll-like receptor family. PMID:38191283 (AGAP006974, fold change 2, p-value 0.0095) PMID:33963082 experiments showed that BmToll9 from the silkmoth Bombyx mori also recognized LPS through interaction with two MD-2-like proteins, |
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Download this section (compressed HTML)Q: Does Anopheles TOLL9 recognize LPS through an MD-2-like partner, an endogenous Spaetzle ligand, or a different input? Distinguish Bombyx ligand evidence from canonical Drosophila Toll assumptions.
Q: Which TIR-dependent partners and physiological immune responses require AGAP006974 itself? mosGILT-dependent transcript changes do not answer receptor necessity or direct activity.
Experiment: Test purified or cell-expressed TOLL9 with candidate LPS/MD-2-like and Spaetzle inputs, then measure receptor-dependent signaling with appropriate accessory-protein controls.
Hypothesis: TOLL9 ligand recognition may resemble the Bombyx Toll9 route or differ from it.
Experiment: Perturb AGAP006974 in mosquitoes and rescue with the wild-type receptor, measuring defined immune outputs and pathogen responses.
Hypothesis: The receptor may contribute to a subset of innate-defense responses rather than every output of the general Toll pathway.
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