TLR5 is a single-pass type I transmembrane pattern recognition receptor of the Toll-like receptor family that detects bacterial flagellin, the structural subunit of the flagellar filament, from both Gram-positive and Gram-negative bacteria. Its extracellular leucine-rich-repeat ectodomain binds a conserved site on monomeric flagellin that is normally buried in the assembled filament and is required for bacterial motility, and TLR5 forms homodimers at the cell surface. Ligand engagement drives receptor activation that, through the intracellular TIR domain and the adaptors MyD88 (and, in intestinal epithelium, TRIF/TICAM1), activates NF-kappaB and MAP kinase signalling and induces proinflammatory cytokines including TNF, IL-6 and IL-8. TLR5 is expressed on the basolateral surface of intestinal epithelia and in lung epithelium and myeloid cells, where it is a key sensor of flagellated bacteria and a regulator of mucosal innate immunity and gut homeostasis. Unlike most cell-surface TLRs, TLR5 requires the chaperone UNC93B1 for proper plasma membrane localization and signalling. A common dominant stop-codon polymorphism (R392STOP) abolishes flagellin signalling and is associated with altered susceptibility to bacterial infection and autoimmune disease.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002224 toll-like receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: TLR5 is a Toll-like receptor whose engagement by flagellin initiates MyD88-dependent innate immune signalling; the general TLR signalling pathway is the correct PAINT-level parent of the TLR5-specific pathway. Reason: Phylogenetically placed at the vertebrate TLR node, which includes TLR5; TLR5 has direct experimental evidence for initiating TLR signalling on flagellin binding. The specific GO:0034146 is annotated separately. Supporting Evidence: PMID:11323673 mammalian TLR5 recognizes bacterial flagellin from both Gram-positive and Gram-negative bacteria, and that activation of the receptor mobilizes the nuclear factor NF-kappaB and stimulates tumour necrosis factor-alpha production PMID:11489966 cell surface expression of Toll-like receptor 5 (TLR5) conferred NF-kappaB gene expression in response to flagellin. The response depended on both extracellular leucine-rich repeats and intracellular Toll/IL-1R homology region of TLR5 as well as the adaptor protein MyD88 |
| GO:0002224 toll-like receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping from the TLR-family signature (IPR017241); TLR5 is a bona fide TLR signalling receptor. Reason: Correct but general; the specific GO:0034146 toll-like receptor 5 signaling pathway captures the core process. Supporting Evidence: PMID:11323673 mammalian TLR5 recognizes bacterial flagellin from both Gram-positive and Gram-negative bacteria, and that activation of the receptor mobilizes the nuclear factor NF-kappaB and stimulates tumour necrosis factor-alpha production |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: TLR5 is a single-pass type I transmembrane receptor that transduces extracellular flagellin binding into intracellular signalling through its TIR domain. Reason: Correct MF from family-level mapping. The more informative pattern recognition receptor activity (GO:0038187) is also annotated and represents the core molecular function. Supporting Evidence: PMID:11489966 cell surface expression of Toll-like receptor 5 (TLR5) conferred NF-kappaB gene expression in response to flagellin. The response depended on both extracellular leucine-rich repeats and intracellular Toll/IL-1R homology region of TLR5 as well as the adaptor protein MyD88 |
| GO:0005149 interleukin-1 receptor binding | IPI PMID:12925853 SIGIRR, a negative regulator of Toll-like receptor-interleuk... | KEEP AS NON CORE | Summary: IPI with SIGIRR/IL-1R8, a TIR-domain IL-1 receptor family member that negatively regulates TLR/IL-1R signalling. Reason: SIGIRR is an IL-1 receptor family protein, so the term is satisfiable, but the interaction reflects negative feedback on TLR/IL-1R signalling rather than an intrinsic function of TLR5. Abstract-only paper; deferring to the curator that TLR5 was among the tested partners. Not a core activity of TLR5. Supporting Evidence: PMID:12925853 biochemical analysis indicated that SIGIRR binds to the TLR-IL-1R signaling components in a ligand-dependent way |
| GO:0005515 protein binding | IPI PMID:30158114 TLR5 decoy receptor as a novel anti-amyloid therapeutic for ... | MODIFY | Summary: IPI with APP-derived amyloid-beta peptides (PRO_0000000092/PRO_0000000093). The cited study shows a soluble TLR5 ectodomain-Fc fusion binds oligomeric and fibrillar amyloid-beta with high affinity by ELISA and biolayer interferometry. Reason: Generic protein binding is uninformative. The paper supports a specific binding activity of the TLR5 ectodomain for amyloid-beta, so the informative replacement is amyloid-beta binding. Demonstrated with an engineered soluble ectodomain decoy; physiological relevance for membrane TLR5 is uncertain, so not a core function. Proposed replacements: amyloid-beta binding Supporting Evidence: PMID:30158114 sTLR5Fc binds to oligomeric and fibrillar AΞ² with high affinity, forms complexes with AΞ², and blocks AΞ² toxicity PMID:30158114 Oligomeric and fibrillar AΞ² modulates flagellin-mediated activation of human TLR5 but does not, by itself, activate TLR5 signaling |
| GO:0005515 protein binding | IPI PMID:30158114 TLR5 decoy receptor as a novel anti-amyloid therapeutic for ... | MODIFY | Summary: IPI with APP-derived amyloid-beta peptides (PRO_0000000092/PRO_0000000093). The cited study shows a soluble TLR5 ectodomain-Fc fusion binds oligomeric and fibrillar amyloid-beta with high affinity by ELISA and biolayer interferometry. Reason: Generic protein binding is uninformative. The paper supports a specific binding activity of the TLR5 ectodomain for amyloid-beta, so the informative replacement is amyloid-beta binding. Demonstrated with an engineered soluble ectodomain decoy; physiological relevance for membrane TLR5 is uncertain, so not a core function. Proposed replacements: amyloid-beta binding Supporting Evidence: PMID:30158114 sTLR5Fc binds to oligomeric and fibrillar AΞ² with high affinity, forms complexes with AΞ², and blocks AΞ² toxicity PMID:30158114 Oligomeric and fibrillar AΞ² modulates flagellin-mediated activation of human TLR5 but does not, by itself, activate TLR5 signaling |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: TLR5 is a cell-surface Toll-like receptor localized at the plasma membrane (basolateral surface in polarized intestinal epithelium). Reason: Consistent with direct evidence on TLR5 itself and with the PAINT placement for cell-surface TLRs. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling PMID:11489966 TLR5 is expressed exclusively on the basolateral surface of intestinal epithelia |
| GO:0005886 plasma membrane | IDA PMID:24778236 UNC93B1 is essential for the plasma membrane localization an... | ACCEPT | Summary: Huh et al. showed TLR5 at the plasma membrane, dependent on UNC93B1. Reason: Direct experimental evidence for plasma membrane localization; also supported by basolateral surface biotinylation of TLR5 in intestinal epithelia. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling PMID:11489966 TLR5 is expressed exclusively on the basolateral surface of intestinal epithelia |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-188025 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: Reactome:R-HSA-188025 Fragments of extracelllar flagellin bind the TLR5 homodimer. PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602316 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602603 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975852 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975853 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975857 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975861 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975865 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975866 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975873 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975874 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975878 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975879 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-975880 | ACCEPT | Summary: Plasma membrane localization of TLR5 (UniProt subcellular-location mapping or Reactome flagellin/TLR5 cascade reaction). Reason: TLR5 is a cell-surface receptor; plasma membrane localization is experimentally supported. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0006955 immune response | IEA GO_REF:0000002 | ACCEPT | Summary: Broad InterPro2GO mapping; TLR5 functions in the innate immune and inflammatory response to flagellated bacteria. Reason: Correct but very general; the specific receptor activity and TLR5 signalling pathway terms carry the informative content. Supporting Evidence: PMID:11323673 mammalian TLR5 recognizes bacterial flagellin from both Gram-positive and Gram-negative bacteria, and that activation of the receptor mobilizes the nuclear factor NF-kappaB and stimulates tumour necrosis factor-alpha production PMID:14623910 a common stop codon polymorphism in the ligand-binding domain of TLR5 (TLR5392STOP) is unable to mediate flagellin signaling |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: TIR-domain-based InterPro2GO mapping to signal transduction. Reason: Correct but general; TLR5 transduces flagellin binding into NF-kappaB activation via TIR-domain adaptors. Supporting Evidence: PMID:11489966 cell surface expression of Toll-like receptor 5 (TLR5) conferred NF-kappaB gene expression in response to flagellin. The response depended on both extracellular leucine-rich repeats and intracellular Toll/IL-1R homology region of TLR5 as well as the adaptor protein MyD88 |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Generic membrane localization from combined IEA methods. Reason: Correct but uninformative; plasma membrane is annotated separately and is the specific location. Supporting Evidence: PMID:24778236 TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling |
| GO:0032757 positive regulation of interleukin-8 production | IDA PMID:17128265 Maintenance of colonic homeostasis by distinctive apical TLR... | KEEP AS NON CORE | Summary: Flagellin/TLR5 signalling in intestinal epithelial cells induces IL-8. The cited PMID:17128265 abstract describes apical/basolateral TLR9 signalling in intestinal epithelium and does not, in the cached abstract, detail the TLR5 IL-8 experiment. Reason: TLR5-driven IL-8 induction in intestinal epithelial cells is well established (e.g. flagellin signalling via TLR5 in EHEC OMV studies). The cached paper is abstract-only; deferring to the curator, who read the full text. This is a downstream inflammatory output, not a core molecular function or process of TLR5. Supporting Evidence: PMID:29934223 The H7 flagellin-mediated signaling via Toll-like receptor (TLR) 5 |
| GO:0034146 toll-like receptor 5 signaling pathway | IDA PMID:14625549 Toll-like receptor 5 recognizes a conserved site on flagelli... | ACCEPT | Summary: TLR5 recognizes bacterial flagellin and initiates the TLR5 signalling pathway leading to inflammatory responses. Reason: Direct experimental demonstration that TLR5 recognizes flagellin and activates host inflammatory responses; this is the core process for TLR5. Supporting Evidence: PMID:14625549 Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and activates host inflammatory responses PMID:11323673 mammalian TLR5 recognizes bacterial flagellin from both Gram-positive and Gram-negative bacteria, and that activation of the receptor mobilizes the nuclear factor NF-kappaB and stimulates tumour necrosis factor-alpha production |
| GO:0034146 toll-like receptor 5 signaling pathway | IDA PMID:17128265 Maintenance of colonic homeostasis by distinctive apical TLR... | ACCEPT | Summary: TLR5 signalling pathway annotation (BHF-UCL, IDA). Reason: The TLR5-specific signalling pathway is the core process of this receptor and is strongly supported experimentally. Deferring to the curator on the specific paper (abstract-only in cache). Supporting Evidence: PMID:14625549 Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and activates host inflammatory responses PMID:11323673 mammalian TLR5 recognizes bacterial flagellin from both Gram-positive and Gram-negative bacteria, and that activation of the receptor mobilizes the nuclear factor NF-kappaB and stimulates tumour necrosis factor-alpha production |
| GO:0038023 signaling receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: TLR5 is a signalling receptor that converts extracellular flagellin binding into an intracellular signal. Reason: IBA at the TLR node; correct and consistent with the more specific pattern recognition receptor activity annotation. Supporting Evidence: PMID:11489966 cell surface expression of Toll-like receptor 5 (TLR5) conferred NF-kappaB gene expression in response to flagellin. The response depended on both extracellular leucine-rich repeats and intracellular Toll/IL-1R homology region of TLR5 as well as the adaptor protein MyD88 |
| GO:0038187 pattern recognition receptor activity | IDA PMID:14625549 Toll-like receptor 5 recognizes a conserved site on flagelli... | ACCEPT | Summary: TLR5 is the pattern recognition receptor for the bacterial PAMP flagellin; monomeric flagellin binds TLR5 and coprecipitates with it, activating NF-kappaB. Reason: Direct experimental evidence that TLR5 recognizes the conserved flagellin PAMP. This is the core molecular function of TLR5. Supporting Evidence: PMID:14625549 flagellin coprecipitated with TLR5, indicating close physical interaction between the molecules file:human/TLR5/TLR5-deep-research-falcon.md The receptor exhibits exquisite specificity for conserved structural determinants within flagellin PMID:11323673 mammalian TLR5 recognizes bacterial flagellin from both Gram-positive and Gram-negative bacteria, and that activation of the receptor mobilizes the nuclear factor NF-kappaB and stimulates tumour necrosis factor-alpha production |
| GO:0038187 pattern recognition receptor activity | IDA PMID:17128265 Maintenance of colonic homeostasis by distinctive apical TLR... | ACCEPT | Summary: TLR5 is the pattern recognition receptor for the bacterial PAMP flagellin; monomeric flagellin binds TLR5 and coprecipitates with it, activating NF-kappaB. Reason: Direct experimental evidence that TLR5 recognizes the conserved flagellin PAMP. This is the core molecular function of TLR5. Supporting Evidence: PMID:14625549 flagellin coprecipitated with TLR5, indicating close physical interaction between the molecules PMID:11323673 mammalian TLR5 recognizes bacterial flagellin from both Gram-positive and Gram-negative bacteria, and that activation of the receptor mobilizes the nuclear factor NF-kappaB and stimulates tumour necrosis factor-alpha production |
| GO:0071260 cellular response to mechanical stimulus | IEP PMID:19593445 Expression of the Bcl-2 protein BAD promotes prostate cancer... | UNDECIDED | Summary: IEP annotation for cellular response to mechanical stimulus citing PMID:19593445. The cached full text of that PMID is "Expression of the Bcl-2 protein BAD promotes prostate cancer growth" (PLoS One), which contains no mention of TLR5, Toll-like receptors, or mechanical stimulus. Reason: The supporting evidence cannot be verified: the cited paper as cached does not concern TLR5 or mechanotransduction, suggesting a mismatched/incorrect PMID for this annotation. Per curation rules, an annotation whose supporting publication cannot be adjudicated is left UNDECIDED. See reference_review flag on PMID:19593445. |
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Download this section (compressed HTML)Q: What is the physiological role, if any, of the TLR5 ectodomain interaction with amyloid-beta for membrane-anchored TLR5 in the brain, as opposed to the engineered soluble decoy receptor?
Q: Why does the cell-surface receptor TLR5, unlike TLR1/2/4/6, require the ER chaperone UNC93B1 for plasma membrane delivery and signalling?
Q: How is the balance between MyD88-dependent and TRIF-dependent TLR5 signalling set in different epithelial and myeloid cell types?
Experiment: Cryo-EM of the full-length TLR5 homodimer bound to monomeric flagellin to define the activated receptor conformation and dimer geometry
Experiment: Cell-type-resolved knockout/rescue of UNC93B1 to quantify its contribution to TLR5 surface delivery and flagellin responsiveness across epithelial and myeloid lineages
Experiment: Structure-guided mutagenesis of the flagellin recognition site to separate ligand binding from downstream MyD88 versus TRIF adaptor recruitment
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