Toll-like receptor 6 (TLR6, CD286) is a type I transmembrane pattern recognition receptor of the TLR1/2/6/10 subfamily, with a leucine-rich repeat ectodomain and a cytoplasmic TIR domain. It functions as an obligate heterodimer partner of TLR2 at the plasma membrane of monocytes, macrophages and dendritic cells: the TLR2:TLR6 heterodimer recognises diacylated bacterial and mycoplasmal lipopeptides (e.g. MALP-2), lipoteichoic acid and other Gram-positive and fungal ligands. In the heterodimer TLR2 binds the lipid chains while TLR6, whose own lipid channel is blocked by two phenylalanines, supplies an extended dimer interface and confers the diacyl specificity that distinguishes it from TLR2:TLR1. Ligand engagement recruits TIR-domain adaptors (TIRAP, MYD88), leading to IRAK/TRAF6 activation, canonical NF-kappaB and MAPK/JNK signalling and inflammatory cytokine production. Activated TLR2:TLR6 clusters with CD14 and CD36 in lipid rafts and is subsequently targeted to the Golgi. TLR6 also forms a CD36-induced heterodimer with TLR4 that mediates sterile inflammatory responses (chemokines, IL-1B priming, ROS, NO) of macrophages and microglia to oxidised LDL and amyloid-beta, signalling through both MYD88 and TICAM1 (TRIF).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001540 amyloid-beta binding | IC PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | REMOVE | Summary: Inferred by curator from TLR6 involvement in cellular responses to amyloid-beta (CD36-TLR4-TLR6 pathway). Reason: The cited study states that the recognition step is performed by CD36, not by the TLRs; amyloid-beta then induces TLR4-TLR6 heterodimerisation downstream of CD36/Src kinase signalling. No direct binding of amyloid-beta to TLR6 was shown, so a binding MF inferred from the process annotation is not supported. The process role is captured by GO:1904646. Supporting Evidence: PMID:20037584 Importantly, we determine that the earliest event in this inflammatory cascade is not ligation of the TLRs but rather CD36-mediated recognition, which signals via Src kinases to induce a previously undescribed TLR heterodimer of TLR4-TLR6. |
| GO:0001774 microglial cell activation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from mouse/rat orthologue: Tlr6-deficient microglia fail to mount inflammatory responses to amyloid-beta. Reason: Microglial activation by fibrillar amyloid-beta requires CD36, TLR4 and TLR6 in mouse microglial cell lines. This is a context-specific (sterile inflammation) role downstream of receptor signalling, not a core function. Supporting Evidence: PMID:20037584 Notably, these inflammatory responses were abrogated in microglia deficient in CD36, TLR4 or TLR6, but not TLR2 |
| GO:0001875 lipopolysaccharide immune receptor activity | IDA PMID:16880211 Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 ... | MODIFY | Summary: TLR6 contributes, as part of the TLR2:TLR6 heterodimer, to a receptor activity for microbial ligands. The cited study examines TLR2/6 responses to diacylated lipoproteins and lipoteichoic acid, not LPS. Reason: TLR2:TLR6 recognises diacylated lipopeptides and related Gram-positive/mycoplasmal ligands; TLR6-deficient cells lose MALP-2 responses only. LPS recognition is the function of TLR4:MD-2 with CD14/LBP, and nothing in the cited abstract implicates TLR6 in LPS sensing. The essence (TLR6 contributes to a pattern recognition receptor activity at the cell surface) is sound, so the LPS-specific child term should be generalised to pattern recognition receptor activity (keeping contributes_to, since recognition requires the TLR2 partner). Proposed replacements: pattern recognition receptor activity Supporting Evidence: PMID:16880211 Our data show that TLR2 forms heterodimers with TLR1 and TLR6 and that these heterodimer pre-exist and are not induced by the ligand. PMID:16880211 Activation occurs at the cell surface, and the observed trafficking is independent of signaling. PMID:11431423 Here we show that TLR6-deficient (TLR6(-/-)) cells are unresponsive to MALP-2 but retain their normal responses to lipopeptides of other bacterial origins. |
| GO:0002224 toll-like receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA placing TLR signaling on the TLR1/2/6/10 clade. Reason: TLR6 is a bona fide TLR that signals as a TLR2:TLR6 heterodimer via its TIR domain. The IBA is consistent with experimental data on TLR6 itself (which appears among the IBA sources). Supporting Evidence: PMID:11431423 these results show that TLR6 recognizes MALP-2 cooperatively with TLR2, and appears to discriminate between the N-terminal lipoylated structures of MALP-2 and lipopeptides derived from other bacteria PMID:10231569 Like other TLR family members, constitutively active TLR6 activates both NF-kappaB and c-Jun N-terminal kinase (JNK). |
| GO:0002224 toll-like receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: InterPro-based electronic annotation (TLR family) to TLR signaling pathway. Reason: Correct for a vertebrate TLR with LRR ectodomain and cytoplasmic TIR domain; more specific TLR6:TLR2 pathway term is annotated separately. Supporting Evidence: PMID:10231569 Human and murine TLR6 are type-I transmembrane receptors that contain both an extracellular leucine-rich repeat (LRR) domain and a cytoplasmic Toll/IL-1 receptor (IL-1R)-like region. |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | IDA PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | ACCEPT | Summary: Tlr6-deficient and Myd88-deficient macrophages fail to induce chemokines/IL-1b in response to oxLDL; TLR4-TLR6 signals via MyD88. Reason: TLR6 signalling, both with TLR2 and with TLR4, is MyD88-dependent through its TIR domain. Supported directly by the cited paper. Supporting Evidence: PMID:20037584 These data demonstrate that TLR4 and TLR6, acting together through MyD88 and TRIF-dependent signaling pathways, are required for macrophage chemokine production in response to atherogenic lipids, invoking the existence of a hitherto undescribed TLR heterodimer. PMID:20037584 In addition to these chemokines, TLR4, TLR6 and MyD88 were also essential for upregulated expression of the cytokine interleukin-1 |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer from mouse Tlr6 (IGI, PMID:20037584). Reason: Consistent with human experimental data; TLR6 signals through MyD88. Supporting Evidence: PMID:20037584 These data demonstrate that TLR4 and TLR6, acting together through MyD88 and TRIF-dependent signaling pathways, are required for macrophage chemokine production in response to atherogenic lipids, invoking the existence of a hitherto undescribed TLR heterodimer. |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Tlr6. Reason: Consistent with human experimental data; TLR6 signals through MyD88. Supporting Evidence: PMID:20037584 These data demonstrate that TLR4 and TLR6, acting together through MyD88 and TRIF-dependent signaling pathways, are required for macrophage chemokine production in response to atherogenic lipids, invoking the existence of a hitherto undescribed TLR heterodimer. |
| GO:0004888 transmembrane signaling receptor activity | IDA PMID:20406817 Identification of Drosophila Yin and PEPT2 as evolutionarily... | ACCEPT | Summary: HEK293T cells transfected with TLR2/6 become responsive to S. aureus (NF-kB reporter); TLR6 contributes to the heterodimeric receptor activity. Reason: Correct but general; the contributes_to qualifier appropriately reflects that TLR6 acts with TLR2. The more informative MF is pattern recognition receptor activity (see core functions). Supporting Evidence: PMID:20406817 we next used HEK293T transfected with TLR2/6 and/or NOD2 and measured NF-ΞΊB activation PMID:20406817 However, when coexpressed with TLR2/6, NOD2 enhanced NFkB activation, indicating that although NOD2 is insufficient for full activation, it synergized with TLR2/6 to increase cytokine response. |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO transmembrane signaling receptor activity. Reason: TLR6 is a type I transmembrane receptor that transduces signals through its TIR domain; general but correct. Supporting Evidence: PMID:10231569 Human and murine TLR6 are type-I transmembrane receptors that contain both an extracellular leucine-rich repeat (LRR) domain and a cytoplasmic Toll/IL-1 receptor (IL-1R)-like region. |
| GO:0005102 signaling receptor binding | IPI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | MODIFY | Summary: Co-immunoprecipitation of TLR6 with TLR4 and CD36 in oxLDL/amyloid-beta stimulated cells. Reason: The partners are TLR4 (a Toll-like receptor) and CD36; the ligand-induced TLR4-TLR6 association is the functionally relevant interaction. Toll-like receptor binding is more informative than generic signaling receptor binding. Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:20037584 Stimulation of THP-1 monocytes with CD36 ligands rapidly induced co-precipitation of CD36 with TLR4 and TLR6 PMID:20037584 Whereas oxLDL markedly augmented co-precipitation of TLR4 and TLR6 in HEK293 cells co-expressing wild-type CD36 |
| GO:0005515 protein binding | IPI PMID:16880211 Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 ... | MODIFY | Summary: IPI with TLR2, CD14 and CD36 (TLR2/6 heterodimer and ligand-induced clusters). Reason: Generic protein binding is uninformative. The paper supports TLR6 heterodimerisation with TLR2, which is captured by Toll-like receptor 2 binding. Proposed replacements: Toll-like receptor 2 binding Supporting Evidence: PMID:16880211 Our data show that TLR2 forms heterodimers with TLR1 and TLR6 and that these heterodimer pre-exist and are not induced by the ligand. PMID:16880211 In contrast, heterotypic associations of TLR2/6 with CD36 are not preformed and are ligand-induced. |
| GO:0005515 protein binding | IPI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | MODIFY | Summary: IPI with TLR4 (CD36-induced TLR4-TLR6 heterodimer). Reason: Generic protein binding is uninformative; the interaction is a ligand-induced TLR4-TLR6 heterodimer, best captured as Toll-like receptor binding. Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:20037584 Whereas oxLDL markedly augmented co-precipitation of TLR4 and TLR6 in HEK293 cells co-expressing wild-type CD36 |
| GO:0005515 protein binding | IPI PMID:20067962 Increased toll-like receptor (TLR) activation and TLR ligand... | MODIFY | Summary: IPI with TLR2 by co-immunoprecipitation from monocytes of diabetic and control subjects. Reason: Generic protein binding is uninformative; the interaction shown is the TLR2/TLR6 association. Proposed replacements: Toll-like receptor 2 binding Supporting Evidence: PMID:20067962 coimmunoprecipitation showed an increased TLR2/TLR6 association in type 2 diabetes |
| GO:0005515 protein binding | IPI PMID:23155421 Isolated Toll-like receptor transmembrane domains are capabl... | MODIFY | Summary: IPI with TLR2 using isolated transmembrane-domain peptides (ToxR, FRET). Reason: Generic protein binding is uninformative; the assay shows heterotypic TLR2-TLR6 transmembrane domain association, consistent with the known heterodimer. Proposed replacements: Toll-like receptor 2 binding Supporting Evidence: PMID:23155421 For heterotypic interactions we saw a FRET signal for both TLR2-TLR1 and TLR2-TLR6 |
| GO:0005515 protein binding | IPI PMID:23155421 Isolated Toll-like receptor transmembrane domains are capabl... | REMOVE | Summary: IPI with TLR1 using isolated transmembrane-domain peptides. Reason: Generic protein binding is uninformative. The TLR1-TLR6 signal comes from isolated transmembrane peptides in a bacterial/micelle system; TLR1 and TLR6 are not known to form a functional receptor pair. Removal does not imply the peptide interaction is false. Supporting Evidence: PMID:23155421 The strongest interactions belonged to the heterotypic interactions among TLR1, TLR2, TLR6, and TLR10 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput AP-MS (BioPlex) interaction with TLR1. Reason: Generic protein binding from a proteome-scale screen is uninformative about TLR6 function; no functional TLR1-TLR6 receptor has been described. |
| GO:0005794 Golgi apparatus | IDA PMID:16880211 Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 ... | KEEP AS NON CORE | Summary: TLR2/6 heterodimers are targeted to the Golgi after ligand-induced raft recruitment. Reason: Ligand-induced trafficking destination; signalling is initiated at the cell surface and the trafficking is independent of signalling. Supporting Evidence: PMID:16880211 All TLR2 receptor clusters accumulate in lipid rafts and are targeted to the Golgi apparatus. PMID:16880211 Activation occurs at the cell surface, and the observed trafficking is independent of signaling. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location mapping to Golgi apparatus. Reason: Based on the same Golgi-targeting observation; a post-stimulation trafficking location, not the site of receptor function. Supporting Evidence: PMID:16880211 All TLR2 receptor clusters accumulate in lipid rafts and are targeted to the Golgi apparatus. |
| GO:0005886 plasma membrane | EXP PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | ACCEPT | Summary: TLR6 detected at the plasma membrane in HEK293 cells. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. Supporting Evidence: PMID:20037584 Minimal co-localization of CD36, TLR4 and TLR6 was seen in resting cells, but upon treatment with oxLDL, CD36, TLR4 and TLR6 co-localized predominantly in intracellular compartments |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA plasma membrane (is_active_in) for the cell-surface TLR clade. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. Supporting Evidence: PMID:33576548 One group is composed of TLR1, TLR2, TLR4, TLR5, TLR6 and poorly characterized TLR10, which are localized to cell membranes and predominantly recognize bacterial components such as lipids, lipoproteins, and proteins. |
| GO:0005886 plasma membrane | IDA PMID:16880211 Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 ... | ACCEPT | Summary: TLR2/6 heterodimers present and activated at the cell surface. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. Supporting Evidence: PMID:16880211 Activation occurs at the cell surface, and the observed trafficking is independent of signaling. |
| GO:0005886 plasma membrane | IDA PMID:20406817 Identification of Drosophila Yin and PEPT2 as evolutionarily... | ACCEPT | Summary: TLR2/6 signals from the plasma membrane in transfected HEK293T cells. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. Supporting Evidence: PMID:20406817 we next used HEK293T transfected with TLR2/6 and/or NOD2 and measured NF-ΞΊB activation |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (cell membrane). Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. Supporting Evidence: PMID:16880211 Activation occurs at the cell surface, and the observed trafficking is independent of signaling. |
| GO:0005886 plasma membrane | NAS PMID:33576548 Structural and functional understanding of the toll-like rec... | ACCEPT | Summary: Review statement that TLR6 is a cell-surface TLR. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. Supporting Evidence: PMID:33576548 One group is composed of TLR1, TLR2, TLR4, TLR5, TLR6 and poorly characterized TLR10, which are localized to cell membranes and predominantly recognize bacterial components such as lipids, lipoproteins, and proteins. |
| GO:0005886 plasma membrane | TAS PMID:10231569 TLR6: A novel member of an expanding toll-like receptor fami... | ACCEPT | Summary: TLR6 described as a type I transmembrane receptor. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. Supporting Evidence: PMID:10231569 Human and murine TLR6 are type-I transmembrane receptors that contain both an extracellular leucine-rich repeat (LRR) domain and a cytoplasmic Toll/IL-1 receptor (IL-1R)-like region. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166072 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166082 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166091 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166119 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166284 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166286 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166362 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166363 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-168950 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2201316 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2201322 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2262775 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2262777 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2559414 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602353 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602383 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602606 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8869667 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937022 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937059 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937079 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9836256 | ACCEPT | Summary: Reactome reaction placing TLR6 (TLR2:TLR6 or TLR4:TLR6 complexes) at the plasma membrane. Reason: TLR6 is a single-pass type I transmembrane receptor that signals from the cell surface as a TLR2:TLR6 heterodimer; plasma membrane localization is well supported experimentally. |
| GO:0006955 immune response | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO immune response. Reason: Correct but unspecific; TLR6 acts in the innate immune response as a pattern recognition receptor partner of TLR2. Proposed replacements: innate immune response Supporting Evidence: PMID:33576548 One group is composed of TLR1, TLR2, TLR4, TLR5, TLR6 and poorly characterized TLR10, which are localized to cell membranes and predominantly recognize bacterial components such as lipids, lipoproteins, and proteins. |
| GO:0006955 immune response | TAS PMID:10426995 Host defense mechanisms triggered by microbial lipoproteins ... | MODIFY | Summary: TAS from a study showing that microbial lipoproteins act through TLRs to induce IL-12 and NO in human macrophages. Reason: Immune response is correct but unspecific; the TLR2-family lipoprotein recognition described is an innate immune response. Proposed replacements: innate immune response Supporting Evidence: PMID:10426995 Here it is shown that microbial lipoproteins are potent stimulators of IL-12 production by human macrophages, and that induction is mediated by Toll-like receptors (TLRs). PMID:10426995 Activation of TLRs by microbial lipoproteins may initiate innate defense mechanisms against infectious pathogens. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO signal transduction (TIR domain). Reason: Very general but correct. Supporting Evidence: PMID:10231569 Like other TLR family members, constitutively active TLR6 activates both NF-kappaB and c-Jun N-terminal kinase (JNK). |
| GO:0007165 signal transduction | TAS PMID:10231569 TLR6: A novel member of an expanding toll-like receptor fami... | ACCEPT | Summary: TAS from the TLR6 cloning paper. Reason: General but correct; constitutively active TLR6 signals to NF-kB and JNK. Supporting Evidence: PMID:10231569 Like other TLR family members, constitutively active TLR6 activates both NF-kappaB and c-Jun N-terminal kinase (JNK). |
| GO:0007250 activation of NF-kappaB-inducing kinase activity | NAS PMID:10231569 TLR6: A novel member of an expanding toll-like receptor fami... | REMOVE | Summary: NAS: activation of NF-kappaB-inducing kinase (NIK) activity, from the TLR6 cloning paper. Reason: The cited paper shows only that constitutively active TLR6 activates NF-kB and JNK reporters; it does not examine NIK. NIK is primarily a non-canonical NF-kB kinase and TLR6 signals via MyD88/IRAK/TRAF6 to canonical NF-kB. The supported role is captured by GO:0043123 positive regulation of canonical NF-kappaB signal transduction. Supporting Evidence: PMID:10231569 Like other TLR family members, constitutively active TLR6 activates both NF-kappaB and c-Jun N-terminal kinase (JNK). |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from mouse Tlr6 (IGI/IMP PMID:20037584, chemokine/cytokine gene induction). Reason: Downstream transcriptional consequence of TLR signalling; very broad regulation term. Supporting Evidence: PMID:20037584 In addition to these chemokines, TLR4, TLR6 and MyD88 were also essential for upregulated expression of the cytokine interleukin-1 |
| GO:0010628 positive regulation of gene expression | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr6. Reason: Downstream transcriptional consequence of TLR signalling; very broad regulation term. Supporting Evidence: PMID:20037584 In addition to these chemokines, TLR4, TLR6 and MyD88 were also essential for upregulated expression of the cytokine interleukin-1 |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: InterPro2GO membrane. Reason: Correct; TLR6 is an integral membrane protein. Supporting Evidence: PMID:10231569 Human and murine TLR6 are type-I transmembrane receptors that contain both an extracellular leucine-rich repeat (LRR) domain and a cytoplasmic Toll/IL-1 receptor (IL-1R)-like region. |
| GO:0030670 phagocytic vesicle membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location (phagosome membrane, by similarity to mouse Tlr6). Reason: TLR2-family receptors are recruited to phagosomes containing Gram-positive bacteria in mouse macrophages; plausible secondary location, not directly tested for human TLR6 in the cached literature. |
| GO:0031663 lipopolysaccharide-mediated signaling pathway | IEA GO_REF:0000108 | REMOVE | Summary: Electronic inference (GO_REF:0000108) from the LPS immune receptor activity annotation. Reason: Derived mechanically from GO:0001875, which is not supported for TLR6 (TLR6-deficient cells lose responses only to diacylated lipopeptide; LPS is sensed by TLR4:MD-2). TLR6 is not a component of the LPS signaling pathway. Supporting Evidence: PMID:11431423 Here we show that TLR6-deficient (TLR6(-/-)) cells are unresponsive to MALP-2 but retain their normal responses to lipopeptides of other bacterial origins. |
| GO:0032493 response to bacterial lipoprotein | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer from mouse Tlr6: response to bacterial lipoprotein. Reason: Core: TLR6 is required for responses to the diacylated lipoprotein MALP-2. Supporting Evidence: PMID:11431423 Here we show that TLR6-deficient (TLR6(-/-)) cells are unresponsive to MALP-2 but retain their normal responses to lipopeptides of other bacterial origins. PMID:11431423 these results show that TLR6 recognizes MALP-2 cooperatively with TLR2, and appears to discriminate between the N-terminal lipoylated structures of MALP-2 and lipopeptides derived from other bacteria |
| GO:0032717 negative regulation of interleukin-8 production | IGI PMID:22198949 TLR2 is a primary receptor for Alzheimer's amyloid Ξ² peptide... | KEEP AS NON CORE | Summary: IGI with TLR2: TLR6 suppresses TLR2-mediated amyloid-beta-triggered inflammatory activation (IL-8 readout). Reason: Context-specific modulatory effect in an amyloid-beta model; abstract-only cached but the direction of the effect is stated. Not a core function. Supporting Evidence: PMID:22198949 TLR2-mediated AΞ²42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6 |
| GO:0032720 negative regulation of tumor necrosis factor production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from mouse Tlr6 (IGI, PMID:22198949): negative regulation of TNF production. Reason: Context-specific modulation of TLR2 responses to amyloid-beta. Supporting Evidence: PMID:22198949 TLR2-mediated AΞ²42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6 |
| GO:0032731 positive regulation of interleukin-1 beta production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from mouse Tlr6 (IDA PMID:23812099): IL-1b production. Reason: Tlr6 is required for IL-1b induction by oxLDL (priming) in macrophages; downstream consequence of signalling. Supporting Evidence: PMID:20037584 In addition to these chemokines, TLR4, TLR6 and MyD88 were also essential for upregulated expression of the cytokine interleukin-1 PMID:23812099 Notably, IL-1Ξ² production was impaired in Cd36β/β, Tlr4β/β and Tlr6β/β macrophages, indicating that this heterotrimeric signaling complex was required for NLRP3 priming by oxLDL. |
| GO:0032731 positive regulation of interleukin-1 beta production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr6. Reason: Tlr6 is required for IL-1b induction by oxLDL (priming); downstream consequence of signalling. Supporting Evidence: PMID:20037584 In addition to these chemokines, TLR4, TLR6 and MyD88 were also essential for upregulated expression of the cytokine interleukin-1 PMID:23812099 Notably, IL-1Ξ² production was impaired in Cd36β/β, Tlr4β/β and Tlr6β/β macrophages, indicating that this heterotrimeric signaling complex was required for NLRP3 priming by oxLDL. |
| GO:0032755 positive regulation of interleukin-6 production | ISS PMID:12077222 Cutting edge: role of Toll-like receptor 1 in mediating immu... | KEEP AS NON CORE | Summary: ISS: IL-6 production in response to diacylated lipopeptide requires TLR6 (mouse). Reason: Cytokine output of TLR2:TLR6 signalling; downstream, not a core function. Supporting Evidence: PMID:12077222 TLR6 associates with TLR2 and recognizes diacylated mycoplasmal lipopeptide along with TLR2. PMID:11431423 Here we show that TLR6-deficient (TLR6(-/-)) cells are unresponsive to MALP-2 but retain their normal responses to lipopeptides of other bacterial origins. |
| GO:0034136 negative regulation of toll-like receptor 2 signaling pathway | IGI PMID:22198949 TLR2 is a primary receptor for Alzheimer's amyloid Ξ² peptide... | KEEP AS NON CORE | Summary: IGI with TLR2: TLR6 suppresses TLR2-mediated amyloid-beta responses. Reason: Context-specific modulatory effect reported in one study; not core. Supporting Evidence: PMID:22198949 TLR2-mediated AΞ²42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6 |
| GO:0035355 Toll-like receptor 2-Toll-like receptor 6 protein complex | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: TLR2-TLR6 protein complex. Reason: Core: TLR6 functions as the TLR2 heterodimer partner. Supporting Evidence: PMID:16880211 Our data show that TLR2 forms heterodimers with TLR1 and TLR6 and that these heterodimer pre-exist and are not induced by the ligand. PMID:19931471 We have determined the crystal structures of TLR2-TLR6-diacylated lipopeptide, TLR2-lipoteichoic acid, and TLR2-PE-DTPA complexes. |
| GO:0035355 Toll-like receptor 2-Toll-like receptor 6 protein complex | IDA PMID:16880211 Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 ... | ACCEPT | Summary: TLR2/6 heterodimers detected at the cell surface. Reason: Core: direct experimental evidence of the heterodimer. Supporting Evidence: PMID:16880211 Our data show that TLR2 forms heterodimers with TLR1 and TLR6 and that these heterodimer pre-exist and are not induced by the ligand. |
| GO:0035355 Toll-like receptor 2-Toll-like receptor 6 protein complex | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer from mouse Tlr6 (IDA PMID:19931471 crystal structure). Reason: Core: the TLR2-TLR6-lipopeptide crystal structure defines the complex. Supporting Evidence: PMID:19931471 We have determined the crystal structures of TLR2-TLR6-diacylated lipopeptide, TLR2-lipoteichoic acid, and TLR2-PE-DTPA complexes. |
| GO:0035355 Toll-like receptor 2-Toll-like receptor 6 protein complex | IPI PMID:23155421 Isolated Toll-like receptor transmembrane domains are capabl... | ACCEPT | Summary: IPI: TLR2-TLR6 transmembrane-domain association. Reason: Consistent with the known heterodimer. Supporting Evidence: PMID:23155421 For heterotypic interactions we saw a FRET signal for both TLR2-TLR1 and TLR2-TLR6 |
| GO:0035663 Toll-like receptor 2 binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: Toll-like receptor 2 binding. Reason: Core: TLR1/6/10 clade members bind TLR2 as heterodimer partners. Supporting Evidence: PMID:16880211 Our data show that TLR2 forms heterodimers with TLR1 and TLR6 and that these heterodimer pre-exist and are not induced by the ligand. |
| GO:0035663 Toll-like receptor 2 binding | IPI PMID:16880211 Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 ... | ACCEPT | Summary: IPI with TLR2. Reason: Core: direct experimental evidence of TLR2 heterodimerisation. Supporting Evidence: PMID:16880211 Our data show that TLR2 forms heterodimers with TLR1 and TLR6 and that these heterodimer pre-exist and are not induced by the ligand. |
| GO:0035666 TRIF-dependent toll-like receptor signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from mouse Tlr6 (IGI PMID:20037584): TRIF-dependent signaling in the TLR4-TLR6 context. Reason: TRIF contributes to TLR4-TLR6 responses to oxLDL/amyloid-beta (e.g. RANTES); TLR2:TLR6 signalling to lipopeptides is MyD88-dependent. Context-specific. Supporting Evidence: PMID:20037584 These data demonstrate that TLR4 and TLR6, acting together through MyD88 and TRIF-dependent signaling pathways, are required for macrophage chemokine production in response to atherogenic lipids, invoking the existence of a hitherto undescribed TLR heterodimer. |
| GO:0035666 TRIF-dependent toll-like receptor signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr6. Reason: TRIF-dependent output limited to the TLR4-TLR6 sterile-inflammation context. Supporting Evidence: PMID:20037584 These data demonstrate that TLR4 and TLR6, acting together through MyD88 and TRIF-dependent signaling pathways, are required for macrophage chemokine production in response to atherogenic lipids, invoking the existence of a hitherto undescribed TLR heterodimer. |
| GO:0038023 signaling receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA signaling receptor activity. Reason: Correct though general; TLR6 contributes to heterodimeric pattern recognition receptor activity with TLR2. Supporting Evidence: PMID:11431423 these results show that TLR6 recognizes MALP-2 cooperatively with TLR2, and appears to discriminate between the N-terminal lipoylated structures of MALP-2 and lipopeptides derived from other bacteria |
| GO:0038023 signaling receptor activity | TAS PMID:10426995 Host defense mechanisms triggered by microbial lipoproteins ... | ACCEPT | Summary: TAS from a study of TLR-mediated responses to microbial lipoproteins. Reason: General but correct for TLR6 as a TLR2 co-receptor for lipoproteins. Supporting Evidence: PMID:10426995 Here it is shown that microbial lipoproteins are potent stimulators of IL-12 production by human macrophages, and that induction is mediated by Toll-like receptors (TLRs). |
| GO:0038124 toll-like receptor TLR6:TLR2 signaling pathway | IDA PMID:16880211 Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 ... | ACCEPT | Summary: TLR2/6 heterodimer signalling from the cell surface in response to its ligand. Reason: Core process for TLR6. Supporting Evidence: PMID:16880211 Our data show that TLR2 forms heterodimers with TLR1 and TLR6 and that these heterodimer pre-exist and are not induced by the ligand. PMID:16880211 Activation occurs at the cell surface, and the observed trafficking is independent of signaling. |
| GO:0038124 toll-like receptor TLR6:TLR2 signaling pathway | IDA PMID:20406817 Identification of Drosophila Yin and PEPT2 as evolutionarily... | ACCEPT | Summary: TLR2/6-transfected HEK293T cells respond to S. aureus. Reason: Core process for TLR6. Supporting Evidence: PMID:20406817 we next used HEK293T transfected with TLR2/6 and/or NOD2 and measured NF-ΞΊB activation |
| GO:0038124 toll-like receptor TLR6:TLR2 signaling pathway | IDA PMID:23626692 Divergent roles of amino acid residues inside and outside th... | ACCEPT | Summary: TLR2/6 responsiveness to diacylated lipopeptide examined with TLR2 TIR mutants (endogenous TLR6 in HEK293T). Reason: Core process; note the paper carries a 2024 expression of concern, but the annotation is independently supported by several other studies. Supporting Evidence: PMID:23626692 the TLR2-TLR6 heterodimer recognizes diacylated lipopeptides from gram-positive bacteria and mycoplasma PMID:23626692 the 681P residue inside of the BB loop exhibited divergent roles in TLR2/2, TLR2/1 and TLR2/6 signalling transduction |
| GO:0042496 detection of diacyl bacterial lipopeptide | IDA PMID:19931471 Recognition of lipopeptide patterns by Toll-like receptor 2-... | ACCEPT | Summary: Crystal structure of the TLR2-TLR6-diacylated lipopeptide complex and mutagenesis of TLR6 lipid-channel phenylalanines. Reason: Core: TLR6 determines ligand discrimination of the heterodimer (its blocked lipid channel restricts recognition to diacylated lipopeptides). Detection requires TLR2, which binds the acyl chains. Supporting Evidence: PMID:19931471 We have determined the crystal structures of TLR2-TLR6-diacylated lipopeptide, TLR2-lipoteichoic acid, and TLR2-PE-DTPA complexes. PMID:19931471 First, the lipid channel of TLR6 is blocked by two phenylalanines. PMID:19931471 Simultaneous mutation of these phenylalanines made TLR2-TLR6 fully responsive not only to diacylated but also to triacylated lipopeptides. |
| GO:0042498 diacyl lipopeptide binding | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer from mouse Tlr6 (IDA PMID:19931471): diacyl lipopeptide binding. Reason: The diacyl lipopeptide is bound by the TLR2:TLR6 heterodimer; the acyl chains insert into TLR2 while TLR6 contributes the dimer interface and shapes specificity. Acceptable as a heterodimer-level binding function. Supporting Evidence: PMID:19931471 We have determined the crystal structures of TLR2-TLR6-diacylated lipopeptide, TLR2-lipoteichoic acid, and TLR2-PE-DTPA complexes. PMID:19931471 Its ligand specificity is controlled by whether it heterodimerizes with TLR1 or TLR6. file:human/TLR6/TLR6-deep-research-falcon.md This structural constraint prevents accommodation of the third (amide-linked) acyl chain characteristic of triacylated lipopeptides, which is instead recognized by TLR1 in the TLR2/TLR1 complex |
| GO:0042742 defense response to bacterium | TAS PMID:10426995 Host defense mechanisms triggered by microbial lipoproteins ... | ACCEPT | Summary: TAS: defense response to bacterium. Reason: TLR2-family lipoprotein sensing initiates antibacterial defence (IL-12, NO). Supporting Evidence: PMID:10426995 Activation of TLRs by microbial lipoproteins may initiate innate defense mechanisms against infectious pathogens. |
| GO:0042802 identical protein binding | IDA PMID:25088687 Crystal structure of TIR domain of TLR6 reveals novel dimeri... | KEEP AS NON CORE | Summary: Crystal structure of the TLR6 TIR domain reveals homodimer interfaces. Reason: Homodimer inferred from crystal packing of the isolated TIR domain; physiological role unclear (TLR6 functions as a heterodimer with TLR2 or TLR4). Supporting Evidence: PMID:25088687 Our structure reveals novel homo-dimerization interfaces, which might be a critical for the interaction with TIR-containing adaptor proteins and itself. |
| GO:0042802 identical protein binding | IPI PMID:23155421 Isolated Toll-like receptor transmembrane domains are capabl... | KEEP AS NON CORE | Summary: IPI: weak homotypic interaction of isolated TLR6 transmembrane peptides. Reason: Weak homotypic interaction in an isolated-peptide assay; TLR6 has no known functional homodimer. Supporting Evidence: PMID:23155421 classify the TLR1 and TLR6 homotypic interactions as weak PMID:23155421 The TLR1, TLR6, and TLR10 receptors are not known to have functional homodimers |
| GO:0043032 positive regulation of macrophage activation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from mouse Tlr6 (IGI PMID:20037584): positive regulation of macrophage activation. Reason: Downstream consequence of TLR4-TLR6 signalling in sterile inflammation. Supporting Evidence: PMID:20037584 These data demonstrate that TLR4 and TLR6, acting together through MyD88 and TRIF-dependent signaling pathways, are required for macrophage chemokine production in response to atherogenic lipids, invoking the existence of a hitherto undescribed TLR heterodimer. |
| GO:0043032 positive regulation of macrophage activation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr6. Reason: Downstream consequence of TLR4-TLR6 signalling in sterile inflammation. Supporting Evidence: PMID:20037584 These data demonstrate that TLR4 and TLR6, acting together through MyD88 and TRIF-dependent signaling pathways, are required for macrophage chemokine production in response to atherogenic lipids, invoking the existence of a hitherto undescribed TLR heterodimer. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IDA PMID:10231569 TLR6: A novel member of an expanding toll-like receptor fami... | ACCEPT | Summary: Constitutively active TLR6 activates NF-kB. Reason: Core downstream output of TLR6 TIR-domain signalling. Supporting Evidence: PMID:10231569 Like other TLR family members, constitutively active TLR6 activates both NF-kappaB and c-Jun N-terminal kinase (JNK). |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IGI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | ACCEPT | Summary: IGI with TLR4/CD36: NF-kB activation by oxLDL/amyloid-beta requires co-expression of TLR4 and TLR6. Reason: Supported directly by reporter assays. Supporting Evidence: PMID:20037584 a 6-fold increase in NF-ΞΊB activation was observed in cells co-expressing TLR4 and TLR6 PMID:20037584 induced a 3-5-fold activation of an NF-ΞΊB-dependent luciferase gene in HEK293 cells co-expressing TLR4 and TLR6 |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IGI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | ACCEPT | Summary: IGI with TLR4/CD36 (second row). Reason: Supported directly by reporter assays. Supporting Evidence: PMID:20037584 a 6-fold increase in NF-ΞΊB activation was observed in cells co-expressing TLR4 and TLR6 |
| GO:0043235 signaling receptor complex | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic annotation to signaling receptor complex. Reason: TLR6 is part of heterodimeric receptor complexes (TLR2:TLR6, CD36-TLR4-TLR6). Supporting Evidence: PMID:16880211 Our data show that TLR2 forms heterodimers with TLR1 and TLR6 and that these heterodimer pre-exist and are not induced by the ligand. |
| GO:0043235 signaling receptor complex | IPI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | ACCEPT | Summary: IPI: CD36-TLR4-TLR6 complex. Reason: Ligand-induced signalling complex shown by co-precipitation. Supporting Evidence: PMID:20037584 Stimulation of THP-1 monocytes with CD36 ligands rapidly induced co-precipitation of CD36 with TLR4 and TLR6 |
| GO:0043235 signaling receptor complex | IPI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | ACCEPT | Summary: IPI: CD36-TLR4-TLR6 complex (second row). Reason: Ligand-induced signalling complex shown by co-precipitation. Supporting Evidence: PMID:20037584 Stimulation of THP-1 monocytes with CD36 ligands rapidly induced co-precipitation of CD36 with TLR4 and TLR6 |
| GO:0043507 positive regulation of JUN kinase activity | IDA PMID:10231569 TLR6: A novel member of an expanding toll-like receptor fami... | KEEP AS NON CORE | Summary: Constitutively active TLR6 activates JNK. Reason: Downstream MAPK output of TLR signalling, shown with a constitutively active construct. Supporting Evidence: PMID:10231569 Like other TLR family members, constitutively active TLR6 activates both NF-kappaB and c-Jun N-terminal kinase (JNK). |
| GO:0045087 innate immune response | NAS PMID:33576548 Structural and functional understanding of the toll-like rec... | ACCEPT | Summary: NAS from a TLR structure/function review. Reason: Correct; TLR6 is an innate immune pattern recognition receptor partner of TLR2. Supporting Evidence: PMID:33576548 One group is composed of TLR1, TLR2, TLR4, TLR5, TLR6 and poorly characterized TLR10, which are localized to cell membranes and predominantly recognize bacterial components such as lipids, lipoproteins, and proteins. |
| GO:0045121 membrane raft | IDA PMID:16880211 Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 ... | ACCEPT | Summary: TLR2/6 heterodimers are recruited into lipid rafts upon ligand stimulation. Reason: Supported directly; ligand-induced location. Supporting Evidence: PMID:16880211 Upon stimulation by the specific ligand, these heterodimers are recruited within lipid rafts. |
| GO:0045121 membrane raft | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (membrane raft). Reason: Supported by the ligand-induced raft recruitment data. Supporting Evidence: PMID:16880211 Upon stimulation by the specific ligand, these heterodimers are recruited within lipid rafts. |
| GO:0045429 positive regulation of nitric oxide biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from mouse Tlr6 (IGI PMID:20037584): NO production by microglia. Reason: Downstream consequence of TLR4-TLR6 signalling. Supporting Evidence: PMID:20037584 consistent with the failure of these microglia to produce IL-1 |
| GO:0045429 positive regulation of nitric oxide biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr6. Reason: Downstream consequence of TLR4-TLR6 signalling. Supporting Evidence: PMID:20037584 consistent with the failure of these microglia to produce IL-1 |
| GO:0046209 nitric oxide metabolic process | IEA GO_REF:0000107 | REMOVE | Summary: Electronic transfer from mouse Tlr6: nitric oxide metabolic process. Reason: TLR6 does not participate in NO metabolism; it signals upstream of NO production. The supported relationship is regulatory and is already captured by GO:0045429 positive regulation of nitric oxide biosynthetic process. Supporting Evidence: PMID:20037584 consistent with the failure of these microglia to produce IL-1 |
| GO:0046982 protein heterodimerization activity | IPI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | KEEP AS NON CORE | Summary: IPI: TLR4-TLR6 heterodimerisation induced by CD36 ligands. Reason: Heterodimerisation is how TLR6 works; the TLR4 partner is specific to the sterile-inflammation context. Better captured as Toll-like receptor binding but acceptable. Supporting Evidence: PMID:20037584 Whereas oxLDL markedly augmented co-precipitation of TLR4 and TLR6 in HEK293 cells co-expressing wild-type CD36 PMID:20037584 Importantly, we determine that the earliest event in this inflammatory cascade is not ligation of the TLRs but rather CD36-mediated recognition, which signals via Src kinases to induce a previously undescribed TLR heterodimer of TLR4-TLR6. |
| GO:0050729 positive regulation of inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from mouse Tlr6 (IGI PMID:20037584). Reason: Downstream consequence of TLR signalling. Supporting Evidence: PMID:20037584 Our results identify CD36-TLR4-TLR6 activation as a common molecular mechanism by which atherogenic lipids and amyloid-beta stimulate sterile inflammation |
| GO:0071723 lipopeptide binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA lipopeptide binding. Reason: Core, at the level of the TLR2:TLR6 heterodimer. Supporting Evidence: PMID:19931471 We have determined the crystal structures of TLR2-TLR6-diacylated lipopeptide, TLR2-lipoteichoic acid, and TLR2-PE-DTPA complexes. |
| GO:0071723 lipopeptide binding | IEA GO_REF:0000120 | ACCEPT | Summary: InterPro2GO lipopeptide binding. Reason: Core, at the level of the TLR2:TLR6 heterodimer. Supporting Evidence: PMID:19931471 We have determined the crystal structures of TLR2-TLR6-diacylated lipopeptide, TLR2-lipoteichoic acid, and TLR2-PE-DTPA complexes. |
| GO:0071723 lipopeptide binding | ISS PMID:11431423 Discrimination of bacterial lipoproteins by Toll-like recept... | ACCEPT | Summary: ISS from mouse Tlr6 knockout: loss of MALP-2 recognition. Reason: Core: TLR6 recognises diacylated lipopeptide cooperatively with TLR2. Supporting Evidence: PMID:11431423 these results show that TLR6 recognizes MALP-2 cooperatively with TLR2, and appears to discriminate between the N-terminal lipoylated structures of MALP-2 and lipopeptides derived from other bacteria PMID:11431423 co-expression of TLR2 and TLR6 is absolutely required for MALP-2 responsiveness |
| GO:0071726 cellular response to diacyl bacterial lipopeptide | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cellular response to diacyl bacterial lipopeptide. Reason: Core process for TLR6. Supporting Evidence: PMID:11431423 Here we show that TLR6-deficient (TLR6(-/-)) cells are unresponsive to MALP-2 but retain their normal responses to lipopeptides of other bacterial origins. |
| GO:0071726 cellular response to diacyl bacterial lipopeptide | IDA PMID:16880211 Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 ... | ACCEPT | Summary: TLR2/6 heterodimer responds to diacylated lipoproteins. Reason: Core process for TLR6. Supporting Evidence: PMID:16880211 Our data show that TLR2 forms heterodimers with TLR1 and TLR6 and that these heterodimer pre-exist and are not induced by the ligand. |
| GO:0071726 cellular response to diacyl bacterial lipopeptide | IDA PMID:19931471 Recognition of lipopeptide patterns by Toll-like receptor 2-... | ACCEPT | Summary: Structure/mutagenesis of TLR2-TLR6 lipopeptide responses. Reason: Core process for TLR6. Supporting Evidence: PMID:19931471 Simultaneous mutation of these phenylalanines made TLR2-TLR6 fully responsive not only to diacylated but also to triacylated lipopeptides. |
| GO:0140052 cellular response to oxidised low-density lipoprotein particle stimulus | IDA PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | KEEP AS NON CORE | Summary: TLR6 is required, with TLR4 and CD36, for chemokine and IL-1b induction by oxLDL. Reason: Well supported but a secondary, sterile-inflammation role that depends on CD36 for recognition. Supporting Evidence: PMID:20037584 These data demonstrate that TLR4 and TLR6, acting together through MyD88 and TRIF-dependent signaling pathways, are required for macrophage chemokine production in response to atherogenic lipids, invoking the existence of a hitherto undescribed TLR heterodimer. PMID:20037584 a 6-fold increase in NF-ΞΊB activation was observed in cells co-expressing TLR4 and TLR6 |
| GO:0140052 cellular response to oxidised low-density lipoprotein particle stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from mouse Tlr6. Reason: Secondary sterile-inflammation role. Supporting Evidence: PMID:20037584 These data demonstrate that TLR4 and TLR6, acting together through MyD88 and TRIF-dependent signaling pathways, are required for macrophage chemokine production in response to atherogenic lipids, invoking the existence of a hitherto undescribed TLR heterodimer. |
| GO:0140052 cellular response to oxidised low-density lipoprotein particle stimulus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr6. Reason: Secondary sterile-inflammation role. Supporting Evidence: PMID:20037584 These data demonstrate that TLR4 and TLR6, acting together through MyD88 and TRIF-dependent signaling pathways, are required for macrophage chemokine production in response to atherogenic lipids, invoking the existence of a hitherto undescribed TLR heterodimer. |
| GO:0140367 antibacterial innate immune response | IDA PMID:20406817 Identification of Drosophila Yin and PEPT2 as evolutionarily... | ACCEPT | Summary: TLR2/6 confers S. aureus responsiveness on HEK293T cells. Reason: Consistent with TLR6 function in sensing Gram-positive bacteria. Supporting Evidence: PMID:20406817 we next used HEK293T transfected with TLR2/6 and/or NOD2 and measured NF-ΞΊB activation PMID:20406817 However, when coexpressed with TLR2/6, NOD2 enhanced NFkB activation, indicating that although NOD2 is insufficient for full activation, it synergized with TLR2/6 to increase cytokine response. |
| GO:1900017 positive regulation of cytokine production involved in inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from mouse Tlr6 (IGI PMID:20037584). Reason: Downstream cytokine output of TLR signalling. Supporting Evidence: PMID:20037584 In addition to these chemokines, TLR4, TLR6 and MyD88 were also essential for upregulated expression of the cytokine interleukin-1 |
| GO:1900017 positive regulation of cytokine production involved in inflammatory response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr6. Reason: Downstream cytokine output of TLR signalling. Supporting Evidence: PMID:20037584 In addition to these chemokines, TLR4, TLR6 and MyD88 were also essential for upregulated expression of the cytokine interleukin-1 |
| GO:1900227 positive regulation of NLRP3 inflammasome complex assembly | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic transfer from mouse Tlr6 (IDA PMID:23812099): positive regulation of NLRP3 inflammasome complex assembly. Reason: The source study shows that CD36-TLR4-TLR6 provides the NF-kB/ROS priming signal (transcription of Nlrp3, Il1b), whereas inflammasome activation (signal 2) comes from CD36-mediated crystal nucleation; IL-1b secretion from LPS-primed Tlr6-deficient macrophages was normal. TLR6 therefore regulates priming, not assembly. Supporting Evidence: PMID:23812099 These data indicate that CD36-TLR4-TLR6, acting via NF-ΞΊB and ROS, primes the NLRP3 inflammasome in response to oxLDL. PMID:23812099 oxLDL-induced IL-1Ξ² secretion from LPS-primed Tlr6β/β macrophages was similar to wild-type macrophages |
| GO:1900227 positive regulation of NLRP3 inflammasome complex assembly | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS from mouse Tlr6. Reason: TLR6 contributes to inflammasome priming, not to complex assembly (see Sheedy et al. 2013). Supporting Evidence: PMID:23812099 These data indicate that CD36-TLR4-TLR6, acting via NF-ΞΊB and ROS, primes the NLRP3 inflammasome in response to oxLDL. PMID:23812099 oxLDL-induced IL-1Ξ² secretion from LPS-primed Tlr6β/β macrophages was similar to wild-type macrophages |
| GO:1903428 positive regulation of reactive oxygen species biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from mouse Tlr6 (IMP PMID:20037584): ROS production in response to oxLDL. Reason: Downstream consequence of TLR4-TLR6 signalling. Supporting Evidence: PMID:20037584 these cells fail to produce ROS when stimulated with oxLDL |
| GO:1903428 positive regulation of reactive oxygen species biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr6. Reason: Downstream consequence of TLR4-TLR6 signalling. Supporting Evidence: PMID:20037584 these cells fail to produce ROS when stimulated with oxLDL |
| GO:1904646 cellular response to amyloid-beta | IDA PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | KEEP AS NON CORE | Summary: Amyloid-beta activates NF-kB in cells co-expressing TLR4 and TLR6. Reason: Secondary sterile-inflammation role; recognition is by CD36. Supporting Evidence: PMID:20037584 induced a 3-5-fold activation of an NF-ΞΊB-dependent luciferase gene in HEK293 cells co-expressing TLR4 and TLR6 PMID:20037584 Importantly, we determine that the earliest event in this inflammatory cascade is not ligation of the TLRs but rather CD36-mediated recognition, which signals via Src kinases to induce a previously undescribed TLR heterodimer of TLR4-TLR6. |
| GO:1904646 cellular response to amyloid-beta | IGI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | KEEP AS NON CORE | Summary: IGI with TLR4/CD36. Reason: Secondary sterile-inflammation role; recognition is by CD36. Supporting Evidence: PMID:20037584 Notably, these inflammatory responses were abrogated in microglia deficient in CD36, TLR4 or TLR6, but not TLR2 |
| GO:2001238 positive regulation of extrinsic apoptotic signaling pathway | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic transfer from mouse Tlr6 (IGI PMID:20037584): neurotoxicity of amyloid-beta-activated microglia. Reason: The source shows that Tlr6-deficient microglia fail to kill co-cultured neurons because they do not produce IL-1b, NO and ROS. Neuronal death is a remote, cell-non-autonomous consequence of microglial signalling; TLR6 does not act in the neurons extrinsic apoptotic pathway. Supporting Evidence: PMID:20037584 consistent with the failure of these microglia to produce IL-1 |
| GO:2001238 positive regulation of extrinsic apoptotic signaling pathway | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS from mouse Tlr6. Reason: Cell-non-autonomous, indirect effect (see IEA row). Supporting Evidence: PMID:20037584 consistent with the failure of these microglia to produce IL-1 |
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Download this section (compressed HTML)Q: GO:0038124 (toll-like receptor TLR6:TLR2 signaling pathway) is a child of GO:0002224 but not of GO:0034150 (toll-like receptor 6 signaling pathway), and no human TLR6 annotation uses GO:0034150. Should the two terms be related (or merged), given that TLR6 has no known ligand-responsive function outside heterodimers with TLR2 or TLR4?
Q: Is there any biochemical evidence that TLR6 itself contacts diacyl lipopeptide (e.g. the peptide or glycerol moiety), or is ligand contact entirely through TLR2, so that lipopeptide binding should be expressed only with contributes_to?
Q: How are the opposing reports reconciled that TLR6 suppresses TLR2-mediated amyloid-beta responses (Liu et al. 2012) but is required, with TLR4 and CD36, for amyloid-beta-induced microglial activation (Stewart et al. 2010)?
Q: Does the TIR-domain homodimer interface seen in the TLR6 TIR crystal structure operate in cells, or is it a crystal-packing interface?
Experiment: Single-particle cryo-EM of full-length TLR2:TLR6 in nanodiscs with diacyl lipopeptide and TIRAP/MYD88, to define the TIR-domain assembly that initiates signalling.
Experiment: Human TLR6-knockout monocyte/macrophage lines (with rescue by the lipid-channel Phe mutant) challenged with diacyl vs triacyl lipopeptides and Gram-positive bacteria, to confirm in human cells the specificity defined in mouse knockouts and structures.
Experiment: Proximity labelling of TLR6 in primary human macrophages before and after oxLDL or amyloid-beta stimulation to test the CD36-TLR4-TLR6 complex endogenously.
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