Toll-like receptor 4 (TLR4) is a type I single-pass transmembrane pattern recognition receptor with an extracellular leucine-rich-repeat ectodomain and a cytoplasmic Toll/interleukin-1 receptor (TIR) domain. It is the signal-transducing receptor for bacterial lipopolysaccharide (LPS): LPS delivered by LBP and CD14 binds the TLR4-MD-2 (LY96) heterodimer, where most of lipid A occupies the MD-2 pocket and the remaining acyl chain and phosphates contact TLR4, bridging two TLR4-MD-2 units into an active dimer. MD-2 is required for TLR4 to reach the cell surface and respond to LPS. Dimerisation brings the TIR domains together to recruit TIR adaptors: at the plasma membrane TIRAP recruits MyD88, leading via IRAK kinases and TRAF6 to NF-kappaB and MAP kinase activation and pro-inflammatory cytokine production; after CD14-dependent endocytosis, TRAM recruits TRIF in endosomes, leading to IRF3 activation and type I interferon production. TLR4 is also engaged by endogenous and non-microbial stimuli, including HMGB1, tenascin-C, nickel and cobalt ions (which induce MD-2-independent homodimerisation), and, through a CD36-regulated TLR4-TLR6 heterodimer, oxidised LDL and amyloid-beta, contributing to sterile inflammation. TLR4 is expressed mainly on monocytes, macrophages, dendritic cells and endothelial cells and on platelets, and is recruited to the phagocytic cup during uptake of Gram-negative bacteria. Common human variants such as Asp299Gly reduce responsiveness to inhaled LPS.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001530 lipopolysaccharide binding | IBA GO_REF:0000033 | ACCEPT | Summary: TLR4 makes direct contacts with LPS within the TLR4-MD-2-LPS complex. Reason: Most of lipid A sits in the MD-2 pocket, but the crystal structure shows the sixth acyl chain and the LPS phosphates contacting TLR4 directly, and photo-crosslinking places LPS on TLR4 as well as MD-2. The PAINT node covers vertebrate TLR4 orthologs with experimental support from rat and human. Accepted; the binding is shared with MD-2 rather than exclusive to TLR4. Supporting Evidence: PMID:19252480 Five of the six lipid chains of LPS are buried deep inside the pocket and the remaining chain is exposed to the surface of MD-2, forming a hydrophobic interaction with the conserved phenylalanines of TLR4 PMID:11274165 Here we show that LPS is cross-linked specifically to TLR4 and MD-2 only when co-expressed with CD14. |
| GO:0001530 lipopolysaccharide binding | IMP PMID:16514062 Lipopolysaccharide from enterohemorrhagic Escherichia coli b... | ACCEPT | Summary: TLR4 is required for binding of E. coli O157 LPS to platelets. Reason: Platelets from Tlr4-deleted mice fail to bind LPS and anti-TLR4 antibodies block human platelet LPS binding. This is consistent with direct LPS contact by the receptor complex; accepted. Supporting Evidence: PMID:16514062 indicating that the TLR4 receptor is required for binding PMID:16514062 Mouse experiments confirmed that O157LPS binding to TLR4 is the primary event leading to platelet activation |
| GO:0001530 lipopolysaccharide binding | NAS PMID:10835634 TLR4 mutations are associated with endotoxin hyporesponsiven... | ACCEPT | Summary: Author statement that TLR4 is the LPS receptor; human TLR4 variants blunt LPS responses. Reason: The NAS statement is consistent with the structural and cross-linking evidence for direct LPS contact by TLR4. Accepted. Supporting Evidence: PMID:10835634 the Asp299Gly mutation (but not the Thr399Ile mutation) interrupts TLR4-mediated LPS signalling PMID:19252480 Five of the six lipid chains of LPS are buried deep inside the pocket and the remaining chain is exposed to the surface of MD-2, forming a hydrophobic interaction with the conserved phenylalanines of TLR4 |
| GO:0001540 amyloid-beta binding | IC PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | REMOVE | Summary: Amyloid-beta binding inferred (IC) from TLR4 participation in the amyloid-beta response. Reason: The source paper assigns ligand binding to the scavenger receptor CD36, not to TLR4: CD36 recognises oxLDL and amyloid-beta and then signals to assemble a TLR4-TLR6 heterodimer. Inferring a binding function for TLR4 from its role in the downstream response contradicts the paper's own model. Supporting Evidence: PMID:20037584 Moreover, our data suggest a new model of TLR heterodimerization, regulated by signals from CD36 that acts as the common ligand binding receptor for oxLDL and Ξ²-amyloid. PMID:20037584 Here we show that oxidized LDL and amyloid-beta trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. |
| GO:0001726 ruffle | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Ruffle localisation transferred by similarity from mouse Tlr4 via UniProt subcellular location. Reason: Plausible for a plasma-membrane receptor distributed at the leading edge of cells, but a minor, context-dependent location not central to receptor function. Supporting Evidence: PMID:12055629 TLR4 was distributed at the leading edge surface of cells in wild-type embryonic fibroblasts |
| GO:0001875 lipopolysaccharide immune receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: TLR4 is the transmembrane, signal-transducing chain of the LPS receptor: it binds LPS together with MD-2 and transmits the signal across the plasma membrane to initiate innate immune signalling. Reason: GO:0001875 is defined as combining with LPS and transmitting the signal across the cell membrane to initiate an innate immune response. Of the three LPS-receptor proteins, only TLR4 spans the membrane and carries the TIR domain that recruits adaptors; MD-2 (LY96) is an extracellular accessory protein and CD14 is GPI-anchored. The TLR4-MD-2-LPS structure shows LPS contacting TLR4 and cross-linking two TLR4-MD-2 units, the dimerisation that activates signalling. This is the anchor MF for TLR4; accepted for both the IBA and the IDA rows. Supporting Evidence: PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:19252480 LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4-MD-2-LPS complex arranged symmetrically PMID:10196138 These data demonstrate that TLR4 is involved in lipopolysaccharide signaling and serves as a cell-surface co-receptor for CD14, leading to lipopolysaccharide-mediated NF-kappaB activation |
| GO:0001875 lipopolysaccharide immune receptor activity | IDA PMID:19252480 The structural basis of lipopolysaccharide recognition by th... | ACCEPT | Summary: TLR4 is the transmembrane, signal-transducing chain of the LPS receptor: it binds LPS together with MD-2 and transmits the signal across the plasma membrane to initiate innate immune signalling. Reason: GO:0001875 is defined as combining with LPS and transmitting the signal across the cell membrane to initiate an innate immune response. Of the three LPS-receptor proteins, only TLR4 spans the membrane and carries the TIR domain that recruits adaptors; MD-2 (LY96) is an extracellular accessory protein and CD14 is GPI-anchored. The TLR4-MD-2-LPS structure shows LPS contacting TLR4 and cross-linking two TLR4-MD-2 units, the dimerisation that activates signalling. This is the anchor MF for TLR4; accepted for both the IBA and the IDA rows. Supporting Evidence: PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:19252480 LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4-MD-2-LPS complex arranged symmetrically PMID:10196138 These data demonstrate that TLR4 is involved in lipopolysaccharide signaling and serves as a cell-surface co-receptor for CD14, leading to lipopolysaccharide-mediated NF-kappaB activation |
| GO:0001891 phagocytic cup | IDA PMID:30883606 The TLR4 adaptor TRAM controls the phagocytosis of Gram-nega... | ACCEPT | Summary: TLR4 is recruited to the phagocytic cup during uptake of E. coli. Reason: Directly shown by imaging in human macrophages; the phagocytic cup is a platform for TRAM-TRIF signalling. Supporting Evidence: PMID:30883606 TLR4 is recruited to the phagocytic cup to provide a platform for subsequent TRAM-TRIF signalling |
| GO:0002224 toll-like receptor signaling pathway | IDA PMID:14607928 Separate functional domains of human MD-2 mediate Toll-like ... | ACCEPT | Summary: TLR4 participates in TLR signalling; MD-2 mutagenesis shows the TLR4-MD-2 complex is needed for LPS responses. Reason: Correct but generic; the more precise TLR4-specific child GO:0034142 toll-like receptor 4 signaling pathway is also annotated to TLR4, so this parent term is kept as-is. Supporting Evidence: PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. PMID:14607928 Disruption of the endogenous MD-2-TLR4 complex by expression of mutant MD-2 inhibited LPS responses in primary human endothelial cells |
| GO:0002224 toll-like receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of TLR signalling from the TLR4 InterPro family. Reason: Correct though general; the TLR4-specific pathway term is also annotated. |
| GO:0002246 wound healing involved in inflammatory response | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Wound healing involved in inflammatory response, transferred electronically from mouse Tlr4. Reason: No evidence available here that TLR4 itself executes a step of wound healing; any role would be indirect, through inflammatory signalling. Over-annotation of a downstream physiological outcome. |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: TLR4 signals through the MyD88-dependent branch (TIRAP/MyD88) from the plasma membrane. Reason: Well established; TIRAP recruits MyD88 to activated TLR4. The TLR4-specific child GO:0035660 would be more precise, but the general term is correct for the IBA and electronic rows. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | IDA PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | ACCEPT | Summary: The CD36-TLR4-TLR6 complex triggers MyD88-dependent signalling in response to oxLDL and amyloid-beta. Reason: Supported by the cited paper; TLR4 is one of the signalling receptors in this pathway. Supporting Evidence: PMID:20037584 Notably, we find that oxLDL induced CD36-TLR4-TLR6 signaling in macrophages triggers a MyD88-dependent chemokine signature similar to that observed in vivo |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | IDA PMID:38670073 Positive selection CRISPR screens reveal a druggable pocket ... | ACCEPT | Summary: CRISPR screens identify TLR4, dependent on OST-A glycosylation, as required for LPS-induced NF-kappaB signalling. Reason: TLR4 is the LPS receptor that initiates MyD88-dependent signalling to NF-kappaB; accepted. Supporting Evidence: PMID:38670073 the LPS receptor Toll-like receptor 4 (TLR4) is specifically dependent on the oligosaccharyltransferase complex OST-A for N-glycosylation and cell-surface localization |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: TLR4 signals through the MyD88-dependent branch (TIRAP/MyD88) from the plasma membrane. Reason: Well established; TIRAP recruits MyD88 to activated TLR4. The TLR4-specific child GO:0035660 would be more precise, but the general term is correct for the IBA and electronic rows. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: TLR4 signals through the MyD88-dependent branch (TIRAP/MyD88) from the plasma membrane. Reason: Well established; TIRAP recruits MyD88 to activated TLR4. The TLR4-specific child GO:0035660 would be more precise, but the general term is correct for the IBA and electronic rows. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. |
| GO:0004888 transmembrane signaling receptor activity | IDA PMID:15618008 TICAM-1 and TICAM-2: toll-like receptor adapters that partic... | ACCEPT | Summary: TLR4 is a single-pass transmembrane receptor that transduces extracellular ligand binding into intracellular signalling. Reason: Correct and appropriately general: besides LPS, TLR4 transduces signals from endogenous ligands (oxLDL/amyloid-beta with CD36 and TLR6, HMGB1, Ni2+). GO:0001875 is not a descendant of this term, so both are informative. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:15618008 TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88-independent DC maturation. |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: TLR4 is a single-pass transmembrane receptor that transduces extracellular ligand binding into intracellular signalling. Reason: Correct and appropriately general: besides LPS, TLR4 transduces signals from endogenous ligands (oxLDL/amyloid-beta with CD36 and TLR6, HMGB1, Ni2+). GO:0001875 is not a descendant of this term, so both are informative. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:15618008 TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88-independent DC maturation. |
| GO:0004888 transmembrane signaling receptor activity | NAS PMID:11970998 Toll-like receptor 4 is required for optimal development of ... | ACCEPT | Summary: TLR4 is a single-pass transmembrane receptor that transduces extracellular ligand binding into intracellular signalling. Reason: Correct and appropriately general: besides LPS, TLR4 transduces signals from endogenous ligands (oxLDL/amyloid-beta with CD36 and TLR6, HMGB1, Ni2+). GO:0001875 is not a descendant of this term, so both are informative. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:15618008 TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88-independent DC maturation. |
| GO:0005102 signaling receptor binding | IPI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | MODIFY | Summary: TLR4 physically associates with TLR6 (and CD36) on oxLDL or amyloid-beta stimulation. Reason: The partner that defines the interaction is another Toll-like receptor; GO:0035325 Toll-like receptor binding is the specific term. The paper shows a TLR4-TLR6 heterodimer. Proposed replacements: Toll-like receptor binding Supporting Evidence: PMID:20037584 Here we show that oxidized LDL and amyloid-beta trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. PMID:20037584 Our work identifies a previously undescribed TLR heterodimer composed of TLR4 and TLR6 that senses these endogenous ligands and initiates innate immune activation of macrophages and microglia. |
| GO:0005515 protein binding | IPI PMID:11441107 Cooperation of Toll-like receptor 2 and 6 for cellular activ... | REMOVE | Summary: TLR4 co-immunoprecipitates with Tollip in HEK293 cells. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. Supporting Evidence: PMID:11441107 we show that Toll-interacting protein (Tollip) coimmunoprecipitates with TLR2 and TLR4 using HEK 293 cells |
| GO:0005515 protein binding | IPI PMID:11544529 Mal (MyD88-adapter-like) is required for Toll-like receptor-... | REMOVE | Summary: Mal/TIRAP associates with TLR4. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. The abstract does not identify the interacting domains, so a TIR domain binding term is not supported by this paper alone. Supporting Evidence: PMID:11544529 Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction. |
| GO:0005515 protein binding | IPI PMID:12925853 SIGIRR, a negative regulator of Toll-like receptor-interleuk... | REMOVE | Summary: SIGIRR binds TLR-IL-1R signalling components. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. Supporting Evidence: PMID:12925853 SIGIRR binds to the TLR-IL-1R signaling components in a ligand-dependent way |
| GO:0005515 protein binding | IPI PMID:15356101 Cutting edge: direct interaction of TLR4 with NAD(P)H oxidas... | REMOVE | Summary: The TLR4 cytoplasmic TIR region binds the C-terminus of NOX4, required for LPS-induced ROS. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. The interaction is via the TIR domain of TLR4 binding a non-TIR region of NOX4, so TIR domain binding would not apply. Supporting Evidence: PMID:15356101 LPS-induced ROS generation and NF-kappaB activation are mediated by a direct interaction of TLR4 with (NAD(P)H oxidase 4 (Nox) 4) PMID:17064675 the cytosolic Toll/IL-1R region of Toll-like receptor 4 (TLR4) (amino acids 739-769) is the responsible domain for interaction with the COOH terminal of Nox4 (amino acids 451-530) |
| GO:0005515 protein binding | IPI PMID:15728506 Human TLR10 is a functional receptor, expressed by B cells a... | REMOVE | Summary: MyD88 interaction reported in a study focused on TLR10. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. Supporting Evidence: PMID:15728506 TLR10 directly associates with MyD88, the common Toll IL-1 receptor domain adapter |
| GO:0005515 protein binding | IPI PMID:15728506 Human TLR10 is a functional receptor, expressed by B cells a... | REMOVE | Summary: TLR4 binds MD-2 (LY96) through its ectodomain, forming the LPS-sensing heterodimer. Reason: Generic protein binding is uninformative. The TLR4-MD-2 association is well established structurally, but its functional content is captured by GO:0046696 lipopolysaccharide receptor complex and GO:0001875; there is no specific MD-2 binding MF term. Supporting Evidence: PMID:17803912 TLR4 and MD-2 form a heterodimer that recognizes LPS (lipopolysaccharide) from Gram-negative bacteria PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules |
| GO:0005515 protein binding | IPI PMID:16622205 The mycobacterial 38-kilodalton glycolipoprotein antigen act... | REMOVE | Summary: TLR4 contributes to monocyte activation by the M. tuberculosis 38-kDa glycolipoprotein. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. Supporting Evidence: PMID:16622205 neutralizing antibodies for Toll-like receptor 2 (TLR2) or TLR4 significantly reduced the ERK1/2 and p38 activation induced by the 38-kDa protein |
| GO:0005515 protein binding | IPI PMID:17064675 Role of NADPH oxidase 4 in lipopolysaccharide-induced proinf... | REMOVE | Summary: The TLR4 cytoplasmic TIR region binds the C-terminus of NOX4, required for LPS-induced ROS. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. The interaction is via the TIR domain of TLR4 binding a non-TIR region of NOX4, so TIR domain binding would not apply. Supporting Evidence: PMID:15356101 LPS-induced ROS generation and NF-kappaB activation are mediated by a direct interaction of TLR4 with (NAD(P)H oxidase 4 (Nox) 4) PMID:17064675 the cytosolic Toll/IL-1R region of Toll-like receptor 4 (TLR4) (amino acids 739-769) is the responsible domain for interaction with the COOH terminal of Nox4 (amino acids 451-530) |
| GO:0005515 protein binding | IPI PMID:17126326 Extracellular heat shock protein 70 mediates heat stress-ind... | REMOVE | Summary: Heat stress and extracellular Hsp70 promote association of TLR2/4 with EGFR. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. Supporting Evidence: PMID:17126326 Both heat stress and pure Hsp70 stimulate activation of TLR2/4 and their association with EGFR. |
| GO:0005515 protein binding | IPI PMID:17258210 MAPPIT analysis of TLR adaptor complexes. | REMOVE | Summary: MAPPIT mammalian two-hybrid mapping of TLR4 interactions with TIR adaptors (TIRAP, TRAM, MyD88). Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. The abstract does not specify TIR-TIR contacts for TLR4, so no more specific term is proposed from this paper. Supporting Evidence: PMID:17258210 We show that the TLR adaptor Mal is critical for linking Myeloid Differentiation primary response protein 88 (MyD88) to TLR2 and TLR4. |
| GO:0005515 protein binding | IPI PMID:17258210 MAPPIT analysis of TLR adaptor complexes. | REMOVE | Summary: MAPPIT mammalian two-hybrid mapping of TLR4 interactions with TIR adaptors (TIRAP, TRAM, MyD88). Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. The abstract does not specify TIR-TIR contacts for TLR4, so no more specific term is proposed from this paper. Supporting Evidence: PMID:17258210 We show that the TLR adaptor Mal is critical for linking Myeloid Differentiation primary response protein 88 (MyD88) to TLR2 and TLR4. |
| GO:0005515 protein binding | IPI PMID:17258210 MAPPIT analysis of TLR adaptor complexes. | REMOVE | Summary: MAPPIT mammalian two-hybrid mapping of TLR4 interactions with TIR adaptors (TIRAP, TRAM, MyD88). Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. The abstract does not specify TIR-TIR contacts for TLR4, so no more specific term is proposed from this paper. Supporting Evidence: PMID:17258210 We show that the TLR adaptor Mal is critical for linking Myeloid Differentiation primary response protein 88 (MyD88) to TLR2 and TLR4. |
| GO:0005515 protein binding | IPI PMID:17803912 Crystal structure of the TLR4-MD-2 complex with bound endoto... | REMOVE | Summary: TLR4 binds MD-2 (LY96) through its ectodomain, forming the LPS-sensing heterodimer. Reason: Generic protein binding is uninformative. The TLR4-MD-2 association is well established structurally, but its functional content is captured by GO:0046696 lipopolysaccharide receptor complex and GO:0001875; there is no specific MD-2 binding MF term. Supporting Evidence: PMID:17803912 TLR4 and MD-2 form a heterodimer that recognizes LPS (lipopolysaccharide) from Gram-negative bacteria PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules |
| GO:0005515 protein binding | IPI PMID:19252480 The structural basis of lipopolysaccharide recognition by th... | REMOVE | Summary: TLR4 binds MD-2 (LY96) through its ectodomain, forming the LPS-sensing heterodimer. Reason: Generic protein binding is uninformative. The TLR4-MD-2 association is well established structurally, but its functional content is captured by GO:0046696 lipopolysaccharide receptor complex and GO:0001875; there is no specific MD-2 binding MF term. Supporting Evidence: PMID:17803912 TLR4 and MD-2 form a heterodimer that recognizes LPS (lipopolysaccharide) from Gram-negative bacteria PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules |
| GO:0005515 protein binding | IPI PMID:19509286 A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP resul... | MODIFY | Summary: TLR4 co-immunoprecipitates with Mal/TIRAP; modelling places the TLR4-binding site on the Mal TIR domain. Reason: The paper supports TLR4 binding the TIR domain of the adaptor Mal, which is captured by GO:0070976 TIR domain binding. Proposed replacements: TIR domain binding Supporting Evidence: PMID:19509286 Like wild type Mal, D96N could be co-immunoprecipitated with both TLR2 and TLR4, indicating that this mutation does not affect the ability of Mal to interact with either of these receptors. PMID:19509286 Modeling of the TIR domains of Mal and Mal D96N suggested that the residue 96 lies away from the TLR4 or TLR2 binding site |
| GO:0005515 protein binding | IPI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | REMOVE | Summary: TLR4 physically associates with TLR6 in the CD36-TLR4-TLR6 complex. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. The TLR6 interaction is represented by GO:0035325 Toll-like receptor binding (proposed for the signaling receptor binding row). Supporting Evidence: PMID:20037584 Our work identifies a previously undescribed TLR heterodimer composed of TLR4 and TLR6 that senses these endogenous ligands and initiates innate immune activation of macrophages and microglia. |
| GO:0005515 protein binding | IPI PMID:20547845 A critical cysteine is required for HMGB1 binding to Toll-li... | REMOVE | Summary: Interaction with MD-2 reported in a study of HMGB1 binding to TLR4. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. Supporting Evidence: PMID:20547845 Surface plasmon resonance studies indicate that HMGB1 binds specifically to TLR4, and that this binding requires a cysteine in position 106. |
| GO:0005515 protein binding | IPI PMID:21383675 Mannan-binding lectin directly interacts with Toll-like rece... | REMOVE | Summary: Mannan-binding lectin binds the TLR4 extracellular domain and attenuates LPS binding. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. Supporting Evidence: PMID:21383675 We also observed that MBL could directly bind to the extracellular domain of TLR4 in a dose-dependent manner |
| GO:0005515 protein binding | IPI PMID:21829704 TIRAP, an adaptor protein for TLR2/4, transduces a signal fr... | MODIFY | Summary: TLR4 binds the TIR adaptors TIRAP, TRAM and MyD88 through its TIR domain. Reason: The paper shows that TIR-domain mutation of TLR4 abolishes adaptor binding; the adaptors are TIR-domain proteins, so GO:0070976 TIR domain binding describes the function. Proposed replacements: TIR domain binding Supporting Evidence: PMID:21829704 Mutations in a protein-protein interaction domain, Toll/IL-1R intracellular domain (TIR), of RAGE and TLR4 (Figures S4B, S4C, and S5C) resulted in abrogation of binding to the adaptor proteins and downstream signal transduction |
| GO:0005515 protein binding | IPI PMID:21829704 TIRAP, an adaptor protein for TLR2/4, transduces a signal fr... | MODIFY | Summary: TLR4 binds the TIR adaptors TIRAP, TRAM and MyD88 through its TIR domain. Reason: The paper shows that TIR-domain mutation of TLR4 abolishes adaptor binding; the adaptors are TIR-domain proteins, so GO:0070976 TIR domain binding describes the function. Proposed replacements: TIR domain binding Supporting Evidence: PMID:21829704 Mutations in a protein-protein interaction domain, Toll/IL-1R intracellular domain (TIR), of RAGE and TLR4 (Figures S4B, S4C, and S5C) resulted in abrogation of binding to the adaptor proteins and downstream signal transduction |
| GO:0005515 protein binding | IPI PMID:21829704 TIRAP, an adaptor protein for TLR2/4, transduces a signal fr... | MODIFY | Summary: TLR4 binds the TIR adaptors TIRAP, TRAM and MyD88 through its TIR domain. Reason: The paper shows that TIR-domain mutation of TLR4 abolishes adaptor binding; the adaptors are TIR-domain proteins, so GO:0070976 TIR domain binding describes the function. Proposed replacements: TIR domain binding Supporting Evidence: PMID:21829704 Mutations in a protein-protein interaction domain, Toll/IL-1R intracellular domain (TIR), of RAGE and TLR4 (Figures S4B, S4C, and S5C) resulted in abrogation of binding to the adaptor proteins and downstream signal transduction |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: High-throughput innate immunity interactome (HI5). Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. Supporting Evidence: PMID:21903422 Fifty-eight baits were associated with 260 interacting proteins |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: High-throughput innate immunity interactome (HI5). Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. Supporting Evidence: PMID:21903422 Fifty-eight baits were associated with 260 interacting proteins |
| GO:0005515 protein binding | IPI PMID:25187624 Broad and direct interaction between TLR and Siglec families... | REMOVE | Summary: TLR4 binds Siglec-5, Siglec-6 and Siglec-9 in a broad TLR-Siglec interaction screen. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. Supporting Evidence: PMID:25187624 Here we report extensive and direct interactions between these pattern recognition receptors. |
| GO:0005515 protein binding | IPI PMID:25187624 Broad and direct interaction between TLR and Siglec families... | REMOVE | Summary: TLR4 binds Siglec-5, Siglec-6 and Siglec-9 in a broad TLR-Siglec interaction screen. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. Supporting Evidence: PMID:25187624 Here we report extensive and direct interactions between these pattern recognition receptors. |
| GO:0005515 protein binding | IPI PMID:25187624 Broad and direct interaction between TLR and Siglec families... | REMOVE | Summary: TLR4 binds Siglec-5, Siglec-6 and Siglec-9 in a broad TLR-Siglec interaction screen. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. Supporting Evidence: PMID:25187624 Here we report extensive and direct interactions between these pattern recognition receptors. |
| GO:0005515 protein binding | IPI PMID:29150600 Mapping tenascin-C interaction with toll-like receptor 4 rev... | REMOVE | Summary: Tenascin-C directly interacts with TLR4 as an endogenous inflammatory trigger. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. The ligand-receptor role is covered by signaling receptor activity. Supporting Evidence: PMID:29150600 Here we map three sites within tenascin-C that directly and cooperatively interact with TLR4. |
| GO:0005515 protein binding | IPI PMID:29190778 MiR-6835 promoted LPS-induced inflammation of HUVECs associa... | REMOVE | Summary: TLR4 interacts with AdipoR1 in lipid rafts of HUVECs. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. Supporting Evidence: PMID:29190778 the interaction between TLR-4 and AdipoR1 in lipid rafts and its mediation role on LPS-induced inflammation was investigated in HUVECs |
| GO:0005515 protein binding | IPI PMID:36232715 PAUF Induces Migration of Human Pancreatic Cancer Cells Excl... | REMOVE | Summary: MyD88 and TRIF co-immunoprecipitate with TLR4 in PAUF-stimulated pancreatic cancer cells. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. No interacting domains were mapped in this paper. Supporting Evidence: PMID:36232715 In the Panc-1_TLR4OE cells, a rapid binding of adaptor MyD88 to TLR4 was observed as early as 10 min after the rPAUF treatment |
| GO:0005515 protein binding | IPI PMID:36232715 PAUF Induces Migration of Human Pancreatic Cancer Cells Excl... | REMOVE | Summary: PAUF (ZG16B) binds TLR4 on pancreatic cancer cells. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. The ligand-receptor role is covered by signaling receptor activity. Supporting Evidence: PMID:36232715 Using TLR4 overexpressed and knockout PC cell lines, we observed direct PAUF-TLR4 binding on the PC cell surfaces |
| GO:0005515 protein binding | IPI PMID:36232715 PAUF Induces Migration of Human Pancreatic Cancer Cells Excl... | REMOVE | Summary: MyD88 and TRIF co-immunoprecipitate with TLR4 in PAUF-stimulated pancreatic cancer cells. Reason: Generic protein binding is uninformative. The reported interaction is not disputed, but the paper does not establish a specific molecular function for TLR4 beyond its receptor activity, which is captured by other annotations. No interacting domains were mapped in this paper. Supporting Evidence: PMID:36232715 In the Panc-1_TLR4OE cells, a rapid binding of adaptor MyD88 to TLR4 was observed as early as 10 min after the rPAUF treatment |
| GO:0005737 cytoplasm | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: TLR4 detected intracellularly in cultured melanocytes. Reason: TLR4 has intracellular biosynthetic and endosomal pools, but cytoplasm is an imprecise location for a transmembrane receptor; kept as non-core. Supporting Evidence: PMID:19740627 Stimulation of melanocytes with TLRs ligands resulted in the release of cytokines (IL-8 and IL-6) and the mRNA accumulation of chemokines (CCL2, CCL3 and CCL5). |
| GO:0005737 cytoplasm | IPI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | KEEP AS NON CORE | Summary: TLR4 internalised with CD36 and TLR6 after ligand stimulation. Reason: Internalisation places TLR4 in endocytic membranes rather than the cytosol; the term is imprecise but not wrong for intracellular pools. Supporting Evidence: PMID:20037584 CD36 and TLR4 are both internalized from the plasma membrane via dynamin-dependent endocytosis |
| GO:0005769 early endosome | IEA GO_REF:0000044 | ACCEPT | Summary: TLR4 is found in early endosomes after LPS-induced endocytosis. Reason: Consistent with LPS-induced relocation of TLR4 with TRAM to endosomes, from where TRIF signalling proceeds. Supporting Evidence: PMID:18222170 LPS induces upregulation of TLR4-association with TRAM and their subsequent translocation into endosome/lysosome |
| GO:0005886 plasma membrane | EXP PMID:17098818 Effects of TREM-1 activation in human neutrophils: activatio... | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | EXP PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | EXP PMID:21393102 TREM-1 interaction with the LPS/TLR4 receptor complex. | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | EXP PMID:36945827 Recombinant human KAI1/CD82 attenuates M1 macrophage polariz... | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | EXP PMID:9237759 A human homologue of the Drosophila Toll protein signals act... | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | IDA PMID:11274165 Lipopolysaccharide is in close proximity to each of the prot... | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | IDA PMID:12055629 Essential role of MD-2 in LPS responsiveness and TLR4 distri... | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | IDA PMID:15027902 Toll-like receptor 2 (TLR2) and TLR4 are present inside huma... | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | IDA PMID:16338228 A molecule that is associated with Toll-like receptor 4 and ... | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | IDA PMID:36232715 PAUF Induces Migration of Human Pancreatic Cancer Cells Excl... | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | IDA PMID:38670073 Positive selection CRISPR screens reveal a druggable pocket ... | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | NAS PMID:33576548 Structural and functional understanding of the toll-like rec... | ACCEPT | Summary: TLR4 is located at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. Supporting Evidence: PMID:9237759 Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166041 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166072 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166082 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166091 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166119 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166284 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166286 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166362 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166363 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2201293 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2201316 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2201322 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2262775 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2262777 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2559414 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5432825 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5432849 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5432852 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602353 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602383 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602606 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6805943 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8869667 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8870678 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937022 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937059 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937079 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9707659 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9836227 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9921458 | ACCEPT | Summary: Reactome places TLR4-containing receptor complexes at the plasma membrane. Reason: TLR4 is a type I single-pass plasma-membrane receptor; the plasma membrane is where it engages LPS with MD-2 and CD14 and signals through TIRAP/MyD88. |
| GO:0006909 phagocytosis | IDA PMID:30883606 The TLR4 adaptor TRAM controls the phagocytosis of Gram-nega... | KEEP AS NON CORE | Summary: TLR4-TRAM-TRIF signalling promotes phagocytosis of Gram-negative bacteria by macrophages. Reason: Supported by the cited paper, but TLR4 acts as a signalling platform that regulates phagocytosis rather than as phagocytic machinery; non-core. Supporting Evidence: PMID:30883606 Our findings demonstrate that TRAM recruitment to this platform requires FIP2 and that TLR4-TRAM-TRIF signalling is needed for phagocytosis. |
| GO:0006954 inflammatory response | IBA GO_REF:0000033 | ACCEPT | Summary: TLR4 initiates the inflammatory response to LPS and to endogenous ligands. Reason: Core biological role; supported experimentally for oxLDL/amyloid-beta and by the IBA placement. Supporting Evidence: PMID:20037584 Our work identifies a previously undescribed TLR heterodimer composed of TLR4 and TLR6 that senses these endogenous ligands and initiates innate immune activation of macrophages and microglia. |
| GO:0006954 inflammatory response | IDA PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | ACCEPT | Summary: TLR4 initiates the inflammatory response to LPS and to endogenous ligands. Reason: Core biological role; supported experimentally for oxLDL/amyloid-beta and by the IBA placement. Supporting Evidence: PMID:20037584 Our work identifies a previously undescribed TLR heterodimer composed of TLR4 and TLR6 that senses these endogenous ligands and initiates innate immune activation of macrophages and microglia. |
| GO:0006954 inflammatory response | IEA GO_REF:0000120 | ACCEPT | Summary: TLR4 initiates the inflammatory response to LPS and to endogenous ligands. Reason: Core biological role; supported experimentally for oxLDL/amyloid-beta and by the IBA placement. Supporting Evidence: PMID:20037584 Our work identifies a previously undescribed TLR heterodimer composed of TLR4 and TLR6 that senses these endogenous ligands and initiates innate immune activation of macrophages and microglia. |
| GO:0006955 immune response | IEA GO_REF:0000002 | ACCEPT | Summary: TLR4 functions in the immune response. Reason: Correct though general. Supporting Evidence: PMID:10426995 Activation of TLRs by microbial lipoproteins may initiate innate defense mechanisms against infectious pathogens. |
| GO:0006955 immune response | TAS PMID:10426995 Host defense mechanisms triggered by microbial lipoproteins ... | ACCEPT | Summary: TLR4 functions in the immune response. Reason: Correct though general. Supporting Evidence: 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: Signal transduction, assigned from the TIR domain. Reason: Correct though general. |
| GO:0009897 external side of plasma membrane | IDA PMID:16514062 Lipopolysaccharide from enterohemorrhagic Escherichia coli b... | ACCEPT | Summary: TLR4 is exposed on the outer surface of platelets. Reason: Detected with antibodies on intact platelets; the LRR ectodomain faces the exterior. Supporting Evidence: PMID:16514062 Platelets express TLR4, as demonstrated in PRP by binding of the anti-TLR4 antibody |
| GO:0009986 cell surface | IDA PMID:25204797 Flotillin-1 facilitates toll-like receptor 3 signaling in hu... | ACCEPT | Summary: TLR4 at the cell surface of human endothelial cells. Reason: Consistent with its plasma-membrane receptor function. |
| GO:0010008 endosome membrane | IDA PMID:18222170 Roles for LPS-dependent interaction and relocation of TLR4 a... | ACCEPT | Summary: TLR4 relocates with TRAM to endosomes after LPS stimulation. Reason: Direct evidence; the endosomal pool is where TRIF signalling is activated. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:18222170 LPS induces upregulation of TLR4-association with TRAM and their subsequent translocation into endosome/lysosome |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-166168 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-166175 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-166245 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-166271 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-168915 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-168921 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-2201293 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-2201338 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-2213017 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-2559568 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-2562541 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-2562564 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-2569057 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-450358 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-5362486 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-5362500 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-936947 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-936951 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-936952 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-936985 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-937029 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-937075 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9823904 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9823906 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9823910 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9823932 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9823934 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9823939 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9824882 | ACCEPT | Summary: Reactome places TLR4-TRAM-TRIF signalling complexes on endosome membranes. Reason: Consistent with experimental evidence that TLR4 is endocytosed after LPS binding and activates TRIF signalling from endosomes. |
| GO:0010572 positive regulation of platelet activation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: LPS binding to platelet TLR4 leads to platelet activation. Reason: Supported by mouse and human platelet data in the cited paper; a specialised cell-type outcome of TLR4 signalling. Supporting Evidence: PMID:16514062 Mouse experiments confirmed that O157LPS binding to TLR4 is the primary event leading to platelet activation |
| GO:0010572 positive regulation of platelet activation | ISS PMID:16514062 Lipopolysaccharide from enterohemorrhagic Escherichia coli b... | KEEP AS NON CORE | Summary: LPS binding to platelet TLR4 leads to platelet activation. Reason: Supported by mouse and human platelet data in the cited paper; a specialised cell-type outcome of TLR4 signalling. Supporting Evidence: PMID:16514062 Mouse experiments confirmed that O157LPS binding to TLR4 is the primary event leading to platelet activation |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of gene expression, transferred from mouse Tlr4. Reason: Correct but very general downstream outcome of TLR4 signalling. |
| GO:0010628 positive regulation of gene expression | IMP PMID:23817958 Proinflammatory stimuli induce galectin-9 in human mesenchym... | KEEP AS NON CORE | Summary: TLR4 ligands induce galectin-9 in human cells. Reason: A downstream transcriptional outcome of TLR4 signalling; non-core. Supporting Evidence: PMID:23817958 ligands of the Toll-like receptors (TLRs) TLR2, TLR3, and TLR4 elicited similar induction of galectin-9 in activated PBMCs |
| GO:0010628 positive regulation of gene expression | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of gene expression, transferred from mouse Tlr4. Reason: Correct but very general downstream outcome of TLR4 signalling. |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: TLR4 is a membrane protein. Reason: Correct though general. |
| GO:0016046 detection of fungus | NAS PMID:11254600 Involvement of CD14 and toll-like receptors in activation of... | MARK AS OVER ANNOTATED | Summary: Author statement that TLR4 may contribute to detection of Aspergillus hyphae. Reason: The authors saw only partial inhibition by anti-TLR4 antibody and state that further studies are needed; this does not establish that TLR4 detects fungi. Supporting Evidence: PMID:11254600 The partial inhibition of hypha-induced activation observed with antibodies against TLR4 and CD14 suggests that several receptors may be involved, of which TLR4 and CD14 are two candidates. |
| GO:0031663 lipopolysaccharide-mediated signaling pathway | IDA NOT PMID:10880523 The toll-like receptor protein RP105 regulates lipopolysacch... | REMOVE | Summary: NOT annotation: human TLR4 expressed alone in Ba/F3 cells does not signal in response to lipid A. Reason: The negative result reflects the absence of the obligate co-receptor MD-2 (or RP105/MD-1), not a lack of function of TLR4. The same paper shows that TLR4 signals LPS when MD-2 or RP105/MD-1 is present (captured by the IGI rows), and TLR4 is required for LPS signalling across many studies. As a NOT statement about the gene product, it is contradicted. Supporting Evidence: PMID:10880523 In contrast to the Ba/F3 cells expressing murine TLR4, the Ba/F3 cells that express human TLR4 alone do not respond to lipid A PMID:10880523 Either MD-2 or RP105βMD-1 is required for LPS recognition and signaling by TLR4. |
| GO:0031663 lipopolysaccharide-mediated signaling pathway | IGI PMID:10880523 The toll-like receptor protein RP105 regulates lipopolysacch... | ACCEPT | Summary: TLR4 mediates LPS signalling together with MD-2 or RP105/MD-1. Reason: Genetic-interaction evidence from the cited paper: LPS signalling via TLR4 depends on MD-2 or RP105/MD-1. Supporting Evidence: PMID:10880523 Either MD-2 or RP105βMD-1 is required for LPS recognition and signaling by TLR4. |
| GO:0031663 lipopolysaccharide-mediated signaling pathway | IGI PMID:10880523 The toll-like receptor protein RP105 regulates lipopolysacch... | ACCEPT | Summary: TLR4 mediates LPS signalling together with MD-2 or RP105/MD-1. Reason: Genetic-interaction evidence from the cited paper: LPS signalling via TLR4 depends on MD-2 or RP105/MD-1. Supporting Evidence: PMID:10880523 Either MD-2 or RP105βMD-1 is required for LPS recognition and signaling by TLR4. |
| GO:0032496 response to lipopolysaccharide | IC PMID:16514062 Lipopolysaccharide from enterohemorrhagic Escherichia coli b... | ACCEPT | Summary: Response to LPS inferred from LPS binding by TLR4. Reason: TLR4 is the signalling receptor for LPS. Supporting Evidence: PMID:16514062 Mouse experiments confirmed that O157LPS binding to TLR4 is the primary event leading to platelet activation |
| GO:0032496 response to lipopolysaccharide | IDA PMID:12594207 Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Stap... | ACCEPT | Summary: TLR4 acts in the response to LPS (LPS control in a study of LTA recognition). Reason: Correct: TLR4 and MD-2 mediate LPS responses, whereas LTA uses TLR2. Supporting Evidence: PMID:10196138 These data demonstrate that TLR4 is involved in lipopolysaccharide signaling and serves as a cell-surface co-receptor for CD14, leading to lipopolysaccharide-mediated NF-kappaB activation |
| GO:0032496 response to lipopolysaccharide | IDA PMID:14607928 Separate functional domains of human MD-2 mediate Toll-like ... | ACCEPT | Summary: The TLR4-MD-2 complex mediates cellular responses to LPS. Reason: Supported by MD-2 mutagenesis data. Supporting Evidence: PMID:14607928 Cellular responses to LPS are mediated by a cell surface receptor complex consisting of Toll-like receptor 4 (TLR4), MD-2, and CD14. PMID:14607928 Disruption of the endogenous MD-2-TLR4 complex by expression of mutant MD-2 inhibited LPS responses in primary human endothelial cells |
| GO:0032497 detection of lipopolysaccharide | IBA GO_REF:0000033 | ACCEPT | Summary: TLR4, with MD-2, detects LPS and converts it into an intracellular signal. Reason: Core process: LPS binding to TLR4-MD-2 induces receptor dimerisation that initiates signalling. Supporting Evidence: PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:19252480 LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4-MD-2-LPS complex arranged symmetrically |
| GO:0032497 detection of lipopolysaccharide | IDA PMID:19252480 The structural basis of lipopolysaccharide recognition by th... | ACCEPT | Summary: TLR4, with MD-2, detects LPS and converts it into an intracellular signal. Reason: Core process: LPS binding to TLR4-MD-2 induces receptor dimerisation that initiates signalling. Supporting Evidence: PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:19252480 LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4-MD-2-LPS complex arranged symmetrically |
| GO:0032497 detection of lipopolysaccharide | IEA GO_REF:0000107 | ACCEPT | Summary: TLR4, with MD-2, detects LPS and converts it into an intracellular signal. Reason: Core process: LPS binding to TLR4-MD-2 induces receptor dimerisation that initiates signalling. Supporting Evidence: PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:19252480 LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4-MD-2-LPS complex arranged symmetrically |
| GO:0032689 negative regulation of type II interferon production | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Negative regulation of cytokine production transferred from mouse Tlr4. Reason: TLR4 activation drives production of these cytokines; the negative-regulation phenotype comes from mouse Tlr4 studies and reflects a context-specific, indirect outcome (e.g. altered immune balance in knockout animals) rather than a function TLR4 executes. It conflicts with the activating role supported on this gene. |
| GO:0032689 negative regulation of type II interferon production | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Negative regulation of cytokine production transferred from mouse Tlr4. Reason: TLR4 activation drives production of these cytokines; the negative-regulation phenotype comes from mouse Tlr4 studies and reflects a context-specific, indirect outcome (e.g. altered immune balance in knockout animals) rather than a function TLR4 executes. It conflicts with the activating role supported on this gene. |
| GO:0032700 negative regulation of interleukin-17 production | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Negative regulation of cytokine production transferred from mouse Tlr4. Reason: TLR4 activation drives production of these cytokines; the negative-regulation phenotype comes from mouse Tlr4 studies and reflects a context-specific, indirect outcome (e.g. altered immune balance in knockout animals) rather than a function TLR4 executes. It conflicts with the activating role supported on this gene. |
| GO:0032700 negative regulation of interleukin-17 production | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Negative regulation of cytokine production transferred from mouse Tlr4. Reason: TLR4 activation drives production of these cytokines; the negative-regulation phenotype comes from mouse Tlr4 studies and reflects a context-specific, indirect outcome (e.g. altered immune balance in knockout animals) rather than a function TLR4 executes. It conflicts with the activating role supported on this gene. |
| GO:0032707 negative regulation of interleukin-23 production | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Negative regulation of cytokine production transferred from mouse Tlr4. Reason: TLR4 activation drives production of these cytokines; the negative-regulation phenotype comes from mouse Tlr4 studies and reflects a context-specific, indirect outcome (e.g. altered immune balance in knockout animals) rather than a function TLR4 executes. It conflicts with the activating role supported on this gene. |
| GO:0032707 negative regulation of interleukin-23 production | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Negative regulation of cytokine production transferred from mouse Tlr4. Reason: TLR4 activation drives production of these cytokines; the negative-regulation phenotype comes from mouse Tlr4 studies and reflects a context-specific, indirect outcome (e.g. altered immune balance in knockout animals) rather than a function TLR4 executes. It conflicts with the activating role supported on this gene. |
| GO:0032715 negative regulation of interleukin-6 production | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Negative regulation of cytokine production transferred from mouse Tlr4. Reason: TLR4 activation drives production of these cytokines; the negative-regulation phenotype comes from mouse Tlr4 studies and reflects a context-specific, indirect outcome (e.g. altered immune balance in knockout animals) rather than a function TLR4 executes. It conflicts with the activating role supported on this gene. |
| GO:0032715 negative regulation of interleukin-6 production | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Negative regulation of cytokine production transferred from mouse Tlr4. Reason: TLR4 activation drives production of these cytokines; the negative-regulation phenotype comes from mouse Tlr4 studies and reflects a context-specific, indirect outcome (e.g. altered immune balance in knockout animals) rather than a function TLR4 executes. It conflicts with the activating role supported on this gene. |
| GO:0032720 negative regulation of tumor necrosis factor production | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Negative regulation of cytokine production transferred from mouse Tlr4. Reason: TLR4 activation drives production of these cytokines; the negative-regulation phenotype comes from mouse Tlr4 studies and reflects a context-specific, indirect outcome (e.g. altered immune balance in knockout animals) rather than a function TLR4 executes. It conflicts with the activating role supported on this gene. |
| GO:0032720 negative regulation of tumor necrosis factor production | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Negative regulation of cytokine production transferred from mouse Tlr4. Reason: TLR4 activation drives production of these cytokines; the negative-regulation phenotype comes from mouse Tlr4 studies and reflects a context-specific, indirect outcome (e.g. altered immune balance in knockout animals) rather than a function TLR4 executes. It conflicts with the activating role supported on this gene. |
| GO:0032722 positive regulation of chemokine production | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: TLR4 ligation induces chemokine production. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:19740627 Stimulation of melanocytes with TLRs ligands resulted in the release of cytokines (IL-8 and IL-6) and the mRNA accumulation of chemokines (CCL2, CCL3 and CCL5). |
| GO:0032722 positive regulation of chemokine production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TLR4 ligation induces chemokine production. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:19740627 Stimulation of melanocytes with TLRs ligands resulted in the release of cytokines (IL-8 and IL-6) and the mRNA accumulation of chemokines (CCL2, CCL3 and CCL5). |
| GO:0032727 positive regulation of interferon-alpha production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of type I and type II interferon production, transferred from mouse Tlr4. Reason: The TRAM-TRIF branch of TLR4 signalling induces type I interferon; these are downstream outputs of the pathway. Supporting Evidence: PMID:15618008 TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88-independent DC maturation. |
| GO:0032727 positive regulation of interferon-alpha production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of type I and type II interferon production, transferred from mouse Tlr4. Reason: The TRAM-TRIF branch of TLR4 signalling induces type I interferon; these are downstream outputs of the pathway. Supporting Evidence: PMID:15618008 TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88-independent DC maturation. |
| GO:0032728 positive regulation of interferon-beta production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of type I and type II interferon production, transferred from mouse Tlr4. Reason: The TRAM-TRIF branch of TLR4 signalling induces type I interferon; these are downstream outputs of the pathway. Supporting Evidence: PMID:15618008 TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88-independent DC maturation. |
| GO:0032728 positive regulation of interferon-beta production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of type I and type II interferon production, transferred from mouse Tlr4. Reason: The TRAM-TRIF branch of TLR4 signalling induces type I interferon; these are downstream outputs of the pathway. Supporting Evidence: PMID:15618008 TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88-independent DC maturation. |
| GO:0032729 positive regulation of type II interferon production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of type I and type II interferon production, transferred from mouse Tlr4. Reason: The TRAM-TRIF branch of TLR4 signalling induces type I interferon; these are downstream outputs of the pathway. Supporting Evidence: PMID:15618008 TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88-independent DC maturation. |
| GO:0032729 positive regulation of type II interferon production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of type I and type II interferon production, transferred from mouse Tlr4. Reason: The TRAM-TRIF branch of TLR4 signalling induces type I interferon; these are downstream outputs of the pathway. Supporting Evidence: PMID:15618008 TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88-independent DC maturation. |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:11432859 Cop, a caspase recruitment domain-containing protein and inh... | KEEP AS NON CORE | Summary: TLR4-dependent LPS-induced IL-1beta secretion in transfected cells. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:11432859 lipopolysaccharide-induced IL-1beta secretion in transfected cells |
| GO:0032731 positive regulation of interleukin-1 beta production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of IL-1 production, transferred from mouse Tlr4. Reason: Downstream output of TLR4 signalling (pro-IL-1beta priming). Supporting Evidence: PMID:20037584 Additionally, CD36-TLR4-TLR6 signaling in macrophages and microglia results in pro-IL1Ξ² transcription, priming these cells for inflammasome activation and IL-1Ξ² secretion. |
| GO:0032731 positive regulation of interleukin-1 beta production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of IL-1 production, transferred from mouse Tlr4. Reason: Downstream output of TLR4 signalling (pro-IL-1beta priming). Supporting Evidence: PMID:20037584 Additionally, CD36-TLR4-TLR6 signaling in macrophages and microglia results in pro-IL1Ξ² transcription, priming these cells for inflammasome activation and IL-1Ξ² secretion. |
| GO:0032732 positive regulation of interleukin-1 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of IL-1 production, transferred from mouse Tlr4. Reason: Downstream output of TLR4 signalling (pro-IL-1beta priming). Supporting Evidence: PMID:20037584 Additionally, CD36-TLR4-TLR6 signaling in macrophages and microglia results in pro-IL1Ξ² transcription, priming these cells for inflammasome activation and IL-1Ξ² secretion. |
| GO:0032732 positive regulation of interleukin-1 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of IL-1 production, transferred from mouse Tlr4. Reason: Downstream output of TLR4 signalling (pro-IL-1beta priming). Supporting Evidence: PMID:20037584 Additionally, CD36-TLR4-TLR6 signaling in macrophages and microglia results in pro-IL1Ξ² transcription, priming these cells for inflammasome activation and IL-1Ξ² secretion. |
| GO:0032733 positive regulation of interleukin-10 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of IL-10 production, transferred from mouse Tlr4. Reason: Downstream output of TLR4 signalling. |
| GO:0032733 positive regulation of interleukin-10 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of IL-10 production, transferred from mouse Tlr4. Reason: Downstream output of TLR4 signalling. |
| GO:0032735 positive regulation of interleukin-12 production | IDA PMID:15027902 Toll-like receptor 2 (TLR2) and TLR4 are present inside huma... | KEEP AS NON CORE | Summary: Intracellular TLR4 signalling is required for IL-12 production by dendritic cells. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:15027902 Depolymerization of the microtubule network disrupted the intracellular expression of TLR2 and TLR4 and profoundly inhibited interleukin-12 (IL-12) production in response to Neisseria meningitidis |
| GO:0032735 positive regulation of interleukin-12 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of IL-12 production, transferred from mouse Tlr4. Reason: Downstream output of TLR4 signalling. |
| GO:0032735 positive regulation of interleukin-12 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of IL-12 production, transferred from mouse Tlr4. Reason: Downstream output of TLR4 signalling. |
| GO:0032755 positive regulation of interleukin-6 production | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: TLR ligands induce IL-6 in melanocytes. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:19740627 Stimulation of melanocytes with TLRs ligands resulted in the release of cytokines (IL-8 and IL-6) and the mRNA accumulation of chemokines (CCL2, CCL3 and CCL5). |
| GO:0032755 positive regulation of interleukin-6 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of IL-6 production, transferred from mouse Tlr4. Reason: Downstream output of TLR4 signalling. |
| GO:0032755 positive regulation of interleukin-6 production | IMP PMID:21329689 MiR-146a inhibits oxidized low-density lipoprotein-induced l... | KEEP AS NON CORE | Summary: TLR4 knockdown via miR-146a reduces oxLDL-induced IL-6 secretion. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:21329689 MiR-146a significantly reduces intracellular LDL cholesterol content and secretion of interleukin 6, interleukin 8, chemokine (C-C motif) ligand 2 and matrix metallopeptidase 9. |
| GO:0032755 positive regulation of interleukin-6 production | IMP PMID:30321456 Differentiation expression of toll-like receptor4 (TLR4) cau... | KEEP AS NON CORE | Summary: TLR4 siRNA reduces IL-6 in monocytes. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:30321456 TLR4, TNF-Ξ± and Interleukin 6 (IL-6) levels in cells were decreased following transfection with miR-140 mimics and TLR4 small interfering RNA. |
| GO:0032757 positive regulation of interleukin-8 production | IDA PMID:17951129 Expression, subcellular localization and cytokinic modulatio... | KEEP AS NON CORE | Summary: TLR4 ligands induce IL-8 in keratinocytes. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:17951129 Keratinocyte activation by TLR2, TLR3, and TLR4 ligands led to the nuclear translocation of NF-kappab and the release of proinflammatory cytokines TNF-alpha and IL-8. |
| GO:0032757 positive regulation of interleukin-8 production | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: TLR ligands induce IL-8 in melanocytes. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:19740627 Stimulation of melanocytes with TLRs ligands resulted in the release of cytokines (IL-8 and IL-6) and the mRNA accumulation of chemokines (CCL2, CCL3 and CCL5). |
| GO:0032757 positive regulation of interleukin-8 production | IDA PMID:21329689 MiR-146a inhibits oxidized low-density lipoprotein-induced l... | KEEP AS NON CORE | Summary: Reducing TLR4 via miR-146a lowers IL-8 secretion. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:21329689 MiR-146a significantly reduces intracellular LDL cholesterol content and secretion of interleukin 6, interleukin 8, chemokine (C-C motif) ligand 2 and matrix metallopeptidase 9. |
| GO:0032760 positive regulation of tumor necrosis factor production | IDA PMID:17951129 Expression, subcellular localization and cytokinic modulatio... | KEEP AS NON CORE | Summary: TLR4 ligands induce TNF-alpha in keratinocytes. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:17951129 Keratinocyte activation by TLR2, TLR3, and TLR4 ligands led to the nuclear translocation of NF-kappab and the release of proinflammatory cytokines TNF-alpha and IL-8. |
| GO:0032760 positive regulation of tumor necrosis factor production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of TNF production, transferred from mouse Tlr4. Reason: Downstream output of TLR4 signalling. |
| GO:0032760 positive regulation of tumor necrosis factor production | IMP PMID:30321456 Differentiation expression of toll-like receptor4 (TLR4) cau... | KEEP AS NON CORE | Summary: TLR4 siRNA reduces TNF-alpha in monocytes. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:30321456 TLR4, TNF-Ξ± and Interleukin 6 (IL-6) levels in cells were decreased following transfection with miR-140 mimics and TLR4 small interfering RNA. |
| GO:0032760 positive regulation of tumor necrosis factor production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of TNF production, transferred from mouse Tlr4. Reason: Downstream output of TLR4 signalling. |
| GO:0034142 toll-like receptor 4 signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: TLR4 is the receptor that initiates the toll-like receptor 4 signaling pathway. Reason: Core process; GO:0034142 is defined as initiated by ligand binding to TLR4, so TLR4 is the defining participant. Supporting Evidence: PMID:19252480 LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4-MD-2-LPS complex arranged symmetrically |
| GO:0034142 toll-like receptor 4 signaling pathway | IDA PMID:10196138 Toll-like receptor-4 mediates lipopolysaccharide-induced sig... | ACCEPT | Summary: LPS/CD14 stimulates NF-kappaB via transfected TLR4. Reason: Direct evidence of TLR4 signalling. Supporting Evidence: PMID:10196138 These data demonstrate that TLR4 is involved in lipopolysaccharide signaling and serves as a cell-surface co-receptor for CD14, leading to lipopolysaccharide-mediated NF-kappaB activation |
| GO:0034142 toll-like receptor 4 signaling pathway | IDA PMID:15618008 TICAM-1 and TICAM-2: toll-like receptor adapters that partic... | ACCEPT | Summary: TLR4 recruits TICAM-1/TICAM-2 to induce type I interferon. Reason: Consistent with TLR4 signalling via TRIF. Supporting Evidence: PMID:15618008 TICAM-1 is the functional adapter for both TLR3 and TLR4 that induces type 1 IFN and MyD88-independent DC maturation. |
| GO:0034142 toll-like receptor 4 signaling pathway | IDA PMID:18222170 Roles for LPS-dependent interaction and relocation of TLR4 a... | ACCEPT | Summary: LPS-induced TLR4-TRAM association and relocation to endosomes activates TRIF signalling. Reason: Direct evidence. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:18222170 LPS induces upregulation of TLR4-association with TRAM and their subsequent translocation into endosome/lysosome |
| GO:0034142 toll-like receptor 4 signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: TLR4 is the receptor that initiates the toll-like receptor 4 signaling pathway. Reason: Core process; GO:0034142 is defined as initiated by ligand binding to TLR4, so TLR4 is the defining participant. Supporting Evidence: PMID:19252480 LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4-MD-2-LPS complex arranged symmetrically |
| GO:0035666 TRIF-dependent toll-like receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: TLR4 signals through the TRAM-TRIF branch from endosomes. Reason: Well established; the TLR4-specific child GO:0035667 would be more precise, but this term is correct. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. file:human/TLR4/TLR4-deep-research-falcon.md into endosomes or phagosomes, where it triggers TRIF-dependent (interferon-producing) signaling |
| GO:0035666 TRIF-dependent toll-like receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: TLR4 signals through the TRAM-TRIF branch from endosomes. Reason: Well established; the TLR4-specific child GO:0035667 would be more precise, but this term is correct. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. file:human/TLR4/TLR4-deep-research-falcon.md into endosomes or phagosomes, where it triggers TRIF-dependent (interferon-producing) signaling |
| GO:0036120 cellular response to platelet-derived growth factor stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Cellular response to PDGF, transferred electronically from mouse Tlr4. Reason: No evidence here that TLR4 executes a step of PDGF signalling; likely an indirect or expression-based observation. |
| GO:0038023 signaling receptor activity | IDA PMID:15618008 TICAM-1 and TICAM-2: toll-like receptor adapters that partic... | ACCEPT | Summary: TLR4 has signaling receptor activity. Reason: Correct; GO-CAM models of TLR4 signalling type TLR4 with this term. It also covers endogenous (non-LPS) ligands. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. |
| GO:0038023 signaling receptor activity | IDA PMID:16751103 Phosphoinositide-mediated adaptor recruitment controls Toll-... | ACCEPT | Summary: TLR4 has signaling receptor activity. Reason: Correct; GO-CAM models of TLR4 signalling type TLR4 with this term. It also covers endogenous (non-LPS) ligands. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. |
| GO:0038023 signaling receptor activity | IDA PMID:18222170 Roles for LPS-dependent interaction and relocation of TLR4 a... | ACCEPT | Summary: TLR4 has signaling receptor activity. Reason: Correct; GO-CAM models of TLR4 signalling type TLR4 with this term. It also covers endogenous (non-LPS) ligands. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. |
| GO:0038023 signaling receptor activity | TAS PMID:10426995 Host defense mechanisms triggered by microbial lipoproteins ... | ACCEPT | Summary: TLR4 has signaling receptor activity. Reason: Correct; GO-CAM models of TLR4 signalling type TLR4 with this term. It also covers endogenous (non-LPS) ligands. Supporting Evidence: PMID:16751103 TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. |
| GO:0042088 T-helper 1 type immune response | NAS PMID:11970998 Toll-like receptor 4 is required for optimal development of ... | MARK AS OVER ANNOTATED | Summary: Author statement linking TLR4 to Th1 responses via IL-12. Reason: The paper actually reports that TLR4 is required for optimal Th2, not Th1, responses to allergen; the Th1 link is an inference the authors set out to test and did not support. Supporting Evidence: PMID:11970998 These results indicate that TLR4 is required for optimal Th2 responses to Ags from nonpathogenic sources |
| GO:0042116 macrophage activation | IMP PMID:10835634 TLR4 mutations are associated with endotoxin hyporesponsiven... | KEEP AS NON CORE | Summary: Alveolar macrophages from TLR4-variant carriers are hyporesponsive to LPS. Reason: Macrophage activation is a downstream outcome of TLR4 signalling. Supporting Evidence: PMID:10835634 the wild-type allele of TLR4 rescues the LPS hyporesponsive phenotype in either primary airway epithelial cells or alveolar macrophages obtained from individuals with the TLR4 mutations |
| GO:0042742 defense response to bacterium | IGI PMID:30321456 Differentiation expression of toll-like receptor4 (TLR4) cau... | ACCEPT | Summary: TLR4 contributes to defence against bacteria. Reason: Correct: TLR4 detects LPS of Gram-negative bacteria. Supporting Evidence: PMID:10426995 Activation of TLRs by microbial lipoproteins may initiate innate defense mechanisms against infectious pathogens. |
| GO:0042742 defense response to bacterium | TAS PMID:10426995 Host defense mechanisms triggered by microbial lipoproteins ... | ACCEPT | Summary: TLR4 contributes to defence against bacteria. Reason: Correct: TLR4 detects LPS of Gram-negative bacteria. Supporting Evidence: PMID:10426995 Activation of TLRs by microbial lipoproteins may initiate innate defense mechanisms against infectious pathogens. |
| GO:0042802 identical protein binding | IPI PMID:23059983 Metal allergens nickel and cobalt facilitate TLR4 homodimeri... | KEEP AS NON CORE | Summary: TLR4 homodimerises on ligand binding (LPS-MD-2 or Ni2+/Co2+). Reason: Ligand-induced homodimerisation is the activation mechanism, so the binding is real and meaningful, but it is a feature of the receptor activity rather than a separate function. Supporting Evidence: PMID:23059983 Experiments with a new TLR4 dimerization mutant established dimerization as a mechanism of metal- and LPS-induced TLR4 activation. PMID:31319868 Binding of LPS causes the TLR4βMD-2 complex dimerization PMID:23155421 All TLR transmembrane domains showed strong homotypic interaction potential. |
| GO:0042802 identical protein binding | IPI PMID:23155421 Isolated Toll-like receptor transmembrane domains are capabl... | KEEP AS NON CORE | Summary: TLR4 homodimerises on ligand binding (LPS-MD-2 or Ni2+/Co2+). Reason: Ligand-induced homodimerisation is the activation mechanism, so the binding is real and meaningful, but it is a feature of the receptor activity rather than a separate function. Supporting Evidence: PMID:23059983 Experiments with a new TLR4 dimerization mutant established dimerization as a mechanism of metal- and LPS-induced TLR4 activation. PMID:31319868 Binding of LPS causes the TLR4βMD-2 complex dimerization PMID:23155421 All TLR transmembrane domains showed strong homotypic interaction potential. |
| GO:0042802 identical protein binding | IPI PMID:31319868 Ciprofloxacin and levofloxacin attenuate microglia inflammat... | KEEP AS NON CORE | Summary: TLR4 homodimerises on ligand binding (LPS-MD-2 or Ni2+/Co2+). Reason: Ligand-induced homodimerisation is the activation mechanism, so the binding is real and meaningful, but it is a feature of the receptor activity rather than a separate function. Supporting Evidence: PMID:23059983 Experiments with a new TLR4 dimerization mutant established dimerization as a mechanism of metal- and LPS-induced TLR4 activation. PMID:31319868 Binding of LPS causes the TLR4βMD-2 complex dimerization PMID:23155421 All TLR transmembrane domains showed strong homotypic interaction potential. |
| GO:0043032 positive regulation of macrophage activation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of macrophage activation, transferred from mouse Tlr4. Reason: Downstream outcome of TLR4 signalling. |
| GO:0043032 positive regulation of macrophage activation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of macrophage activation, transferred from mouse Tlr4. Reason: Downstream outcome of TLR4 signalling. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IDA PMID:16968406 Nicotine inhibits the production of proinflammatory mediator... | ACCEPT | Summary: LPS/TLR4-induced NF-kappaB activation in monocytes (nicotine study). Reason: Downstream NF-kappaB activation by TLR4 is well established; this paper provides only indirect support. Accepted for consistency with the other rows for this term; NF-kappaB activation is the principal output of TLR4 signalling. Supporting Evidence: PMID:16968406 LPS/TLR4 signalling induces IKK activation, which leads eventually to the NF-ΞΊB translocation and activation |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | ACCEPT | Summary: TLR ligation in melanocytes activates NF-kappaB. Reason: NF-kappaB activation is the principal output of TLR4 signalling. Supporting Evidence: PMID:19740627 Triggering of TLRs in melanocytes resulted in the up-regulation of phosphorylated IkappaBalpha and in the nucleus translocation of NF-kappaBp65. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IGI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | ACCEPT | Summary: The CD36-TLR4-TLR6 complex activates NF-kappaB in response to amyloid-beta and oxLDL. Reason: Supported by the cited paper. Supporting Evidence: PMID:20037584 Notably, TLR4-TLR6-mediated NF-ΞΊB activation occurred in the absence of MD-2 |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IGI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | ACCEPT | Summary: The CD36-TLR4-TLR6 complex activates NF-kappaB in response to amyloid-beta and oxLDL. Reason: Supported by the cited paper. Supporting Evidence: PMID:20037584 Notably, TLR4-TLR6-mediated NF-ΞΊB activation occurred in the absence of MD-2 |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IMP PMID:30233718 Reduced peripheral blood miR-140 may be a biomarker for acut... | ACCEPT | Summary: TLR4 silencing suppresses NF-kappaB phosphorylation (miR-140 study). Reason: Consistent with TLR4 upstream of NF-kappaB; indirect. Accepted for consistency with the other rows for this term; NF-kappaB activation is the principal output of TLR4 signalling. Supporting Evidence: PMID:30233718 It was revealed that TLR4 silencing was able to suppress the phosphorylation of NF-ΞΊB even in cells transfected with miR-140 inhibitor. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | ISS GO_REF:0000024 | ACCEPT | Summary: Positive regulation of canonical NF-kappaB signalling, transferred from mouse Tlr4. Reason: Principal output of TLR4 signalling. Supporting Evidence: PMID:9237759 a constitutively active mutant of human Toll transfected into human cell lines can induce the activation of NF-kappaB and the expression of NF-kappaB-controlled genes for the inflammatory cytokines IL-1, IL-6 and IL-8 |
| GO:0043235 signaling receptor complex | IEA GO_REF:0000107 | ACCEPT | Summary: TLR4 is part of signalling receptor complexes (TLR4-MD-2 and CD36-TLR4-TLR6). Reason: Supported structurally and biochemically. Supporting Evidence: PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:20037584 Our work identifies a previously undescribed TLR heterodimer composed of TLR4 and TLR6 that senses these endogenous ligands and initiates innate immune activation of macrophages and microglia. |
| GO:0043235 signaling receptor complex | IPI PMID:19252480 The structural basis of lipopolysaccharide recognition by th... | ACCEPT | Summary: TLR4 is part of signalling receptor complexes (TLR4-MD-2 and CD36-TLR4-TLR6). Reason: Supported structurally and biochemically. Supporting Evidence: PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:20037584 Our work identifies a previously undescribed TLR heterodimer composed of TLR4 and TLR6 that senses these endogenous ligands and initiates innate immune activation of macrophages and microglia. |
| GO:0043235 signaling receptor complex | IPI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | ACCEPT | Summary: TLR4 is part of signalling receptor complexes (TLR4-MD-2 and CD36-TLR4-TLR6). Reason: Supported structurally and biochemically. Supporting Evidence: PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:20037584 Our work identifies a previously undescribed TLR heterodimer composed of TLR4 and TLR6 that senses these endogenous ligands and initiates innate immune activation of macrophages and microglia. |
| GO:0043235 signaling receptor complex | IPI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | ACCEPT | Summary: TLR4 is part of signalling receptor complexes (TLR4-MD-2 and CD36-TLR4-TLR6). Reason: Supported structurally and biochemically. Supporting Evidence: PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:20037584 Our work identifies a previously undescribed TLR heterodimer composed of TLR4 and TLR6 that senses these endogenous ligands and initiates innate immune activation of macrophages and microglia. |
| GO:0045087 innate immune response | IEA GO_REF:0000107 | ACCEPT | Summary: TLR4 is a key receptor of the innate immune response. Reason: Core process. Supporting Evidence: PMID:33576548 Activation of TLRs induces production of pro-inflammatory cytokines and type I interferons PMID:15356140 stimulation of quiescent microglia with various TLR agonists, including LPS (TLR4), peptidoglycan (TLR2), polyinosinic-polycytidylic acid (TLR3), CpG DNA (TLR9), and infection with viable Theiler's murine encephalomyelitis virus, activated the cells to up-regulate unique patterns of innate and effector immune cytokines and chemokines |
| GO:0045087 innate immune response | NAS PMID:33576548 Structural and functional understanding of the toll-like rec... | ACCEPT | Summary: TLR4 is a key receptor of the innate immune response. Reason: Core process. Supporting Evidence: PMID:33576548 Activation of TLRs induces production of pro-inflammatory cytokines and type I interferons PMID:15356140 stimulation of quiescent microglia with various TLR agonists, including LPS (TLR4), peptidoglycan (TLR2), polyinosinic-polycytidylic acid (TLR3), CpG DNA (TLR9), and infection with viable Theiler's murine encephalomyelitis virus, activated the cells to up-regulate unique patterns of innate and effector immune cytokines and chemokines |
| GO:0045087 innate immune response | TAS PMID:15356140 Microglia initiate central nervous system innate and adaptiv... | ACCEPT | Summary: TLR4 is a key receptor of the innate immune response. Reason: Core process. Supporting Evidence: PMID:33576548 Activation of TLRs induces production of pro-inflammatory cytokines and type I interferons PMID:15356140 stimulation of quiescent microglia with various TLR agonists, including LPS (TLR4), peptidoglycan (TLR2), polyinosinic-polycytidylic acid (TLR3), CpG DNA (TLR9), and infection with viable Theiler's murine encephalomyelitis virus, activated the cells to up-regulate unique patterns of innate and effector immune cytokines and chemokines |
| GO:0045321 leukocyte activation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Leukocyte activation, ARBA electronic assignment. Reason: General downstream outcome of TLR4 signalling. |
| GO:0045429 positive regulation of nitric oxide biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of nitric oxide biosynthesis, transferred from mouse Tlr4. Reason: LPS induction of NO synthase through TLR signalling is a downstream output. Supporting Evidence: PMID:10426995 Activation of TLRs by microbial lipoproteins may initiate innate defense mechanisms against infectious pathogens. |
| GO:0045671 negative regulation of osteoclast differentiation | NAS PMID:12133979 Stimulation by toll-like receptors inhibits osteoclast diffe... | KEEP AS NON CORE | Summary: TLR stimulation inhibits osteoclast differentiation of mouse precursors. Reason: Pan-TLR ligand study; a context-specific downstream outcome. Supporting Evidence: PMID:12133979 TLR stimulation of osteoclast precursors by these microbial products strongly inhibited their differentiation into multinucleated, mature osteoclasts |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:12594207 Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Stap... | MARK AS OVER ANNOTATED | Summary: Positive regulation of transcription by RNA polymerase II. Reason: TLR4 is a membrane receptor several steps removed from transcription; the transcriptional effects belong to NF-kappaB/IRF transcription factors. Over-annotation of a distal outcome. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of transcription by RNA polymerase II. Reason: TLR4 is a membrane receptor several steps removed from transcription; the transcriptional effects belong to NF-kappaB/IRF transcription factors. Over-annotation of a distal outcome. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Positive regulation of transcription by RNA polymerase II. Reason: TLR4 is a membrane receptor several steps removed from transcription; the transcriptional effects belong to NF-kappaB/IRF transcription factors. Over-annotation of a distal outcome. |
| GO:0046696 lipopolysaccharide receptor complex | IBA GO_REF:0000033 | ACCEPT | Summary: TLR4 is a core component of the LPS receptor complex with MD-2 and CD14. Reason: Core location/complex, supported by cross-linking and crystallography. Supporting Evidence: PMID:11274165 Here we show that LPS is cross-linked specifically to TLR4 and MD-2 only when co-expressed with CD14. PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules |
| GO:0046696 lipopolysaccharide receptor complex | IDA PMID:11274165 Lipopolysaccharide is in close proximity to each of the prot... | ACCEPT | Summary: TLR4 is a core component of the LPS receptor complex with MD-2 and CD14. Reason: Core location/complex, supported by cross-linking and crystallography. Supporting Evidence: PMID:11274165 Here we show that LPS is cross-linked specifically to TLR4 and MD-2 only when co-expressed with CD14. PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules |
| GO:0046696 lipopolysaccharide receptor complex | IDA PMID:19252480 The structural basis of lipopolysaccharide recognition by th... | ACCEPT | Summary: TLR4 is a core component of the LPS receptor complex with MD-2 and CD14. Reason: Core location/complex, supported by cross-linking and crystallography. Supporting Evidence: PMID:11274165 Here we show that LPS is cross-linked specifically to TLR4 and MD-2 only when co-expressed with CD14. PMID:19252480 Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules |
| GO:0046982 protein heterodimerization activity | IPI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | KEEP AS NON CORE | Summary: TLR4 heterodimerises with TLR6 in response to CD36 ligands. Reason: Supported; a non-canonical, CD36-dependent receptor configuration. Supporting Evidence: PMID:20037584 Our work identifies a previously undescribed TLR heterodimer composed of TLR4 and TLR6 that senses these endogenous ligands and initiates innate immune activation of macrophages and microglia. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:15027902 Toll-like receptor 2 (TLR2) and TLR4 are present inside huma... | KEEP AS NON CORE | Summary: TLR4 concentrated in a perinuclear region of dendritic cells. Reason: Reflects intracellular (Golgi-associated) pools of the receptor; non-core. Supporting Evidence: PMID:15027902 We show here that TLR2 and TLR4 are expressed inside DCs in an abundant tubulovesicular pattern with a focus of intense staining adjacent to the nucleus. |
| GO:0050727 regulation of inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Regulation of inflammatory response, transferred from mouse Tlr4. Reason: Correct though general. |
| GO:0050729 positive regulation of inflammatory response | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: TLR ligation promotes inflammatory responses. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:19740627 Stimulation of melanocytes with TLRs ligands resulted in the release of cytokines (IL-8 and IL-6) and the mRNA accumulation of chemokines (CCL2, CCL3 and CCL5). |
| GO:0050729 positive regulation of inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TLR ligation promotes inflammatory responses. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:19740627 Stimulation of melanocytes with TLRs ligands resulted in the release of cytokines (IL-8 and IL-6) and the mRNA accumulation of chemokines (CCL2, CCL3 and CCL5). |
| GO:0050729 positive regulation of inflammatory response | IMP PMID:21329689 MiR-146a inhibits oxidized low-density lipoprotein-induced l... | KEEP AS NON CORE | Summary: Reducing TLR4 lowers oxLDL-induced inflammatory responses. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:21329689 miR-146a inhibits the activation of TLR4-dependent intracellular signaling pathways involved in cytoskeleton rearrangement, lipid uptake, and inflammatory cytokine secretion |
| GO:0050829 defense response to Gram-negative bacterium | IBA GO_REF:0000033 | ACCEPT | Summary: TLR4 is required for defence against Gram-negative bacteria through LPS detection. Reason: Core biological role. Supporting Evidence: PMID:16514062 Mouse experiments confirmed that O157LPS binding to TLR4 is the primary event leading to platelet activation PMID:10835634 the Asp299Gly mutation (but not the Thr399Ile mutation) interrupts TLR4-mediated LPS signalling |
| GO:0050829 defense response to Gram-negative bacterium | IC PMID:16514062 Lipopolysaccharide from enterohemorrhagic Escherichia coli b... | ACCEPT | Summary: TLR4 is required for defence against Gram-negative bacteria through LPS detection. Reason: Core biological role. Supporting Evidence: PMID:16514062 Mouse experiments confirmed that O157LPS binding to TLR4 is the primary event leading to platelet activation PMID:10835634 the Asp299Gly mutation (but not the Thr399Ile mutation) interrupts TLR4-mediated LPS signalling |
| GO:0060729 intestinal epithelial structure maintenance | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Intestinal epithelial structure maintenance, transferred from mouse Tlr4. Reason: Plausible tissue-level outcome of TLR4 sensing of commensal bacteria in mouse; non-core. |
| GO:0060729 intestinal epithelial structure maintenance | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Intestinal epithelial structure maintenance, transferred from mouse Tlr4. Reason: Plausible tissue-level outcome of TLR4 sensing of commensal bacteria in mouse; non-core. |
| GO:0070373 negative regulation of ERK1 and ERK2 cascade | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Negative regulation of ERK1/2 cascade, transferred from mouse Tlr4. Reason: TLR4 activates rather than inhibits MAPK/ERK signalling; a negative effect would be context-specific and indirect. Supporting Evidence: PMID:16622205 neutralizing antibodies for Toll-like receptor 2 (TLR2) or TLR4 significantly reduced the ERK1/2 and p38 activation induced by the 38-kDa protein |
| GO:0070373 negative regulation of ERK1 and ERK2 cascade | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Negative regulation of ERK1/2 cascade, transferred from mouse Tlr4. Reason: TLR4 activates rather than inhibits MAPK/ERK signalling; a negative effect would be context-specific and indirect. Supporting Evidence: PMID:16622205 neutralizing antibodies for Toll-like receptor 2 (TLR2) or TLR4 significantly reduced the ERK1/2 and p38 activation induced by the 38-kDa protein |
| GO:0071222 cellular response to lipopolysaccharide | IDA PMID:11432859 Cop, a caspase recruitment domain-containing protein and inh... | ACCEPT | Summary: Cellular response to LPS. Reason: TLR4 is the LPS receptor. Supporting Evidence: PMID:11432859 lipopolysaccharide-induced IL-1beta secretion in transfected cells |
| GO:0071222 cellular response to lipopolysaccharide | IGI PMID:30321456 Differentiation expression of toll-like receptor4 (TLR4) cau... | ACCEPT | Summary: TLR4 levels (regulated by miR-140) determine monocyte responses to LPS. Reason: Consistent with TLR4 as the LPS receptor. Supporting Evidence: PMID:30321456 TLR4, TNF-Ξ± and Interleukin 6 (IL-6) levels in cells were decreased following transfection with miR-140 mimics and TLR4 small interfering RNA. |
| GO:0071222 cellular response to lipopolysaccharide | ISS GO_REF:0000024 | ACCEPT | Summary: Cellular response to LPS, transferred from mouse Tlr4. Reason: TLR4 is the LPS receptor. Supporting Evidence: PMID:10196138 These data demonstrate that TLR4 is involved in lipopolysaccharide signaling and serves as a cell-surface co-receptor for CD14, leading to lipopolysaccharide-mediated NF-kappaB activation |
| GO:0071260 cellular response to mechanical stimulus | IEP PMID:19593445 Expression of the Bcl-2 protein BAD promotes prostate cancer... | UNDECIDED | Summary: Cellular response to mechanical stimulus (IEP) attributed to a paper on BAD in prostate cancer. Reason: The cached full text of PMID:19593445 does not mention TLR4, Toll-like receptors or mechanical stimulation, so the supporting evidence cannot be located; this may be a reference error in the source record. Left undecided rather than removed. |
| GO:0071346 cellular response to type II interferon | IDA PMID:11672593 Toll-like receptor 2 and 4 surface expressions on human mono... | MARK AS OVER ANNOTATED | Summary: IFN-gamma up-regulates TLR4 surface expression on monocytes. Reason: The evidence shows TLR4 as a target of IFN-gamma (expression change), not TLR4 executing the response to IFN-gamma. Supporting Evidence: PMID:11672593 IFN-gamma up-regulated both TLR2 and TLR4 |
| GO:0120163 negative regulation of cold-induced thermogenesis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: TLR4 activation attenuates adaptive thermogenesis in mouse adipose tissue. Reason: Supported as a physiological consequence of TLR4-driven inflammation and ER stress, but an indirect systemic outcome rather than a function of TLR4. Supporting Evidence: PMID:26370079 Collectively, our data indicate the existence of a novel signaling network that links TLR4 activation, ER stress, and mitochondrial dysfunction, thereby antagonizing thermogenic activation of sWAT. |
| GO:0120163 negative regulation of cold-induced thermogenesis | ISS PMID:26370079 Activation of Toll-like receptor 4 (TLR4) attenuates adaptiv... | MARK AS OVER ANNOTATED | Summary: TLR4 activation attenuates adaptive thermogenesis in mouse adipose tissue. Reason: Supported as a physiological consequence of TLR4-driven inflammation and ER stress, but an indirect systemic outcome rather than a function of TLR4. Supporting Evidence: PMID:26370079 Collectively, our data indicate the existence of a novel signaling network that links TLR4 activation, ER stress, and mitochondrial dysfunction, thereby antagonizing thermogenic activation of sWAT. |
| 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: TLR4 (with TLR6 and CD36) mediates inflammatory signalling in response to oxLDL. Reason: Supported; a sterile-inflammation role secondary to LPS sensing. Supporting Evidence: PMID:20037584 Here we show that oxidized LDL and amyloid-beta trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. |
| GO:0140052 cellular response to oxidised low-density lipoprotein particle stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TLR4 (with TLR6 and CD36) mediates inflammatory signalling in response to oxLDL. Reason: Supported; a sterile-inflammation role secondary to LPS sensing. Supporting Evidence: PMID:20037584 Here we show that oxidized LDL and amyloid-beta trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. |
| GO:0140052 cellular response to oxidised low-density lipoprotein particle stimulus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: TLR4 (with TLR6 and CD36) mediates inflammatory signalling in response to oxLDL. Reason: Supported; a sterile-inflammation role secondary to LPS sensing. Supporting Evidence: PMID:20037584 Here we show that oxidized LDL and amyloid-beta trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. |
| GO:1900017 positive regulation of cytokine production involved in inflammatory response | IDA PMID:16968406 Nicotine inhibits the production of proinflammatory mediator... | KEEP AS NON CORE | Summary: LPS/TLR4-induced cytokine production in monocytes. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:16968406 LPS/TLR4 signalling induces IKK activation, which leads eventually to the NF-ΞΊB translocation and activation |
| GO:1900017 positive regulation of cytokine production involved in inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of cytokine production in the inflammatory response, transferred from mouse Tlr4. Reason: Downstream output of TLR4 signalling. |
| GO:1900017 positive regulation of cytokine production involved in inflammatory response | IMP PMID:30321456 Differentiation expression of toll-like receptor4 (TLR4) cau... | KEEP AS NON CORE | Summary: TLR4 siRNA reduces TNF-alpha and IL-6 in monocytes. Reason: Downstream output. Supporting Evidence: PMID:30321456 TLR4, TNF-Ξ± and Interleukin 6 (IL-6) levels in cells were decreased following transfection with miR-140 mimics and TLR4 small interfering RNA. |
| GO:1900017 positive regulation of cytokine production involved in inflammatory response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of cytokine production in the inflammatory response, transferred from mouse Tlr4. Reason: Downstream output of TLR4 signalling. |
| GO:1900227 positive regulation of NLRP3 inflammasome complex assembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TLR4 signalling primes the NLRP3 inflammasome. Reason: TLR4 signalling induces pro-IL-1beta transcription that primes inflammasome activation; a downstream regulatory role. Supporting Evidence: PMID:20037584 Additionally, CD36-TLR4-TLR6 signaling in macrophages and microglia results in pro-IL1Ξ² transcription, priming these cells for inflammasome activation and IL-1Ξ² secretion. |
| GO:1900227 positive regulation of NLRP3 inflammasome complex assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: TLR4 signalling primes the NLRP3 inflammasome. Reason: TLR4 signalling induces pro-IL-1beta transcription that primes inflammasome activation; a downstream regulatory role. Supporting Evidence: PMID:20037584 Additionally, CD36-TLR4-TLR6 signaling in macrophages and microglia results in pro-IL1Ξ² transcription, priming these cells for inflammasome activation and IL-1Ξ² secretion. |
| GO:1903428 positive regulation of reactive oxygen species biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TLR4 signalling promotes ROS production. Reason: Supported by the TLR4-NOX4 interaction required for LPS-induced ROS generation. Supporting Evidence: PMID:15356101 LPS-induced ROS generation and NF-kappaB activation are mediated by a direct interaction of TLR4 with (NAD(P)H oxidase 4 (Nox) 4) |
| GO:1903428 positive regulation of reactive oxygen species biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: TLR4 signalling promotes ROS production. Reason: Supported by the TLR4-NOX4 interaction required for LPS-induced ROS generation. Supporting Evidence: PMID:15356101 LPS-induced ROS generation and NF-kappaB activation are mediated by a direct interaction of TLR4 with (NAD(P)H oxidase 4 (Nox) 4) |
| GO:1903974 positive regulation of cellular response to macrophage colony-stimulating factor stimulus | IDA PMID:11672593 Toll-like receptor 2 and 4 surface expressions on human mono... | REMOVE | Summary: TLR4 annotated to positive regulation of the cellular response to M-CSF. Reason: The cited study shows the reverse direction: M-CSF up-regulates TLR4 surface expression on monocytes. TLR4 is the target of M-CSF signalling here, not a regulator of the response to it. Supporting Evidence: PMID:11672593 M-CSF up-regulated both TLR2 and TLR4 surface expression on human peripheral blood monocytes |
| GO:1904466 positive regulation of matrix metallopeptidase secretion | IMP PMID:21329689 MiR-146a inhibits oxidized low-density lipoprotein-induced l... | KEEP AS NON CORE | Summary: Reducing TLR4 via miR-146a lowers MMP9 secretion by oxLDL-treated macrophages. Reason: Downstream output of TLR4 signalling. Supporting Evidence: PMID:21329689 MiR-146a significantly reduces intracellular LDL cholesterol content and secretion of interleukin 6, interleukin 8, chemokine (C-C motif) ligand 2 and matrix metallopeptidase 9. |
| GO:1904646 cellular response to amyloid-beta | IDA PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | KEEP AS NON CORE | Summary: TLR4 (with TLR6 and CD36) mediates inflammatory signalling in response to amyloid-beta. Reason: Supported; sterile-inflammation role. Supporting Evidence: PMID:20037584 Here we show that oxidized LDL and amyloid-beta trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. |
| GO:1904646 cellular response to amyloid-beta | IGI PMID:20037584 CD36 ligands promote sterile inflammation through assembly o... | KEEP AS NON CORE | Summary: TLR4 (with TLR6 and CD36) mediates inflammatory signalling in response to amyloid-beta. Reason: Supported; sterile-inflammation role. Supporting Evidence: PMID:20037584 Here we show that oxidized LDL and amyloid-beta trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. |
| GO:2000343 positive regulation of chemokine (C-X-C motif) ligand 2 production | IMP PMID:21329689 MiR-146a inhibits oxidized low-density lipoprotein-induced l... | KEEP AS NON CORE | Summary: Reducing TLR4 lowers chemokine secretion by oxLDL-treated macrophages. Reason: Downstream output. Supporting Evidence: PMID:21329689 miR-146a inhibits the activation of TLR4-dependent intracellular signaling pathways involved in cytoskeleton rearrangement, lipid uptake, and inflammatory cytokine secretion |
| GO:2001238 positive regulation of extrinsic apoptotic signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of extrinsic apoptotic signalling, transferred from mouse Tlr4. Reason: Plausible downstream outcome of TLR4-TRIF signalling in some cell types; non-core. |
| GO:2001238 positive regulation of extrinsic apoptotic signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of extrinsic apoptotic signalling, transferred from mouse Tlr4. Reason: Plausible downstream outcome of TLR4-TRIF signalling in some cell types; non-core. |
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Download this section (compressed HTML)Q: GO:0001875 lipopolysaccharide immune receptor activity is annotated with `enables` to TLR4, LY96 (MD-2) and CD14. Since the definition requires transmitting the signal across the membrane, which only TLR4 does, should MD-2 and CD14 instead carry `contributes_to` GO:0001875 (or LPS binding / a carrier activity), leaving `enables` to TLR4?
Q: Should ligand-class-specific receptor MFs be created for TLR4 non-LPS ligands (e.g. HMGB1, which already has GO:0070380 high mobility group box 1 receptor activity), or is generic signaling receptor activity with has_input in GO-CAM the intended pattern?
Q: The IEP row for GO:0071260 cites PMID:19593445, whose full text does not discuss TLR4. Which publication was intended?
Experiment: Reconstitute human TLR4 with MD-2 or CD14 omitted, and with TIR-domain point mutants, in TLR4-null cells to separate the LPS-contact, signal-transmission and adaptor-recruitment contributions of TLR4 from those of its co-receptors.
Experiment: Measure direct binding of HMGB1, tenascin-C and PAUF to purified TLR4 ectodomain with and without MD-2 by an orthogonal biophysical method, to establish which endogenous ligands TLR4 itself recognises.
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