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Details on Person UniProt:O00206 TLR4
| Class:Id | ReferenceGeneProduct:66107 |
|---|---|
| _chainChangeLog | signal peptide:1-23 added on Sat February 7 2015;chain:24-839 added on Sat February 7 2015 |
| _displayName | UniProt:O00206 TLR4 |
| _timestamp | 2026-02-20 22:27:48 |
| chain | signal peptide:1-23 chain:24-839 |
| checksum | 92C48F55821133E8 |
| comment | FUNCTION Transmembrane receptor that functions as a pattern recognition receptor recognizing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) to induce innate immune responses via downstream signaling pathways (PubMed:10835634, PubMed:15809303, PubMed:16622205, PubMed:17292937, PubMed:17478729, PubMed:20037584, PubMed:20711192, PubMed:23880187, PubMed:27022195, PubMed:29038465, PubMed:17803912, PubMed:15852007). At the plasma membrane, cooperates with LY96 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+) (PubMed:20711192). Mechanistically, acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:10835634, PubMed:21393102, PubMed:27022195, PubMed:36945827, PubMed:9237759). Alternatively, CD14-mediated TLR4 internalization via endocytosis is associated with the initiation of a MYD88-independent signaling via the TICAM1-TBK1-IRF3 axis leading to type I interferon production (PubMed:14517278). In addition to the secretion of proinflammatory cytokines, initiates the activation of NLRP3 inflammasome and formation of a positive feedback loop between autophagy and NF-kappa-B signaling cascade (PubMed:32894580). In complex with TLR6, promotes inflammation in monocytes/macrophages by associating with TLR6 and the receptor CD86 (PubMed:23880187). Upon ligand binding, such as oxLDL or amyloid-beta 42, the TLR4:TLR6 complex is internalized and triggers inflammatory response, leading to NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway (PubMed:23880187). In myeloid dendritic cells, vesicular stomatitis virus glycoprotein G but not LPS promotes the activation of IRF7, leading to type I IFN production in a CD14-dependent manner (PubMed:15265881, PubMed:23880187). Required for the migration-promoting effects of ZG16B/PAUF on pancreatic cancer cells.SUBUNIT Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4 (PubMed:11274165). Binding to bacterial LPS leads to homodimerization. Interacts with LY96 via the extracellular domain (PubMed:17803912, PubMed:19252480). Interacts with MYD88 (PubMed:36232715). Interacts (via TIR domains) with TIRAP (By similarity). Interacts with TICAM2 (PubMed:14519765, PubMed:25736436). Interacts with NOX4 (PubMed:15356101). Interacts with CNPY3 (By similarity). Interacts with HSP90B1. The interaction with both CNPY3 and HSP90B1 is required for proper folding in the endoplasmic reticulum. Interacts with MAP3K21; this interaction leads to negative regulation of TLR4 signaling (PubMed:21602844). Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR6 (PubMed:20037584). The trimeric complex is internalized and triggers inflammatory response. LYN kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Interacts with TICAM1 in response to LPS in a WDFY1-dependent manner (PubMed:25736436, PubMed:36232715). Interacts with WDFY1 in response to LPS (By similarity). Interacts with SMPDL3B (By similarity). Interacts with CEACAM1; upon lipopolysaccharide stimulation, forms a complex including TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the production of reactive oxygen species (ROS) and lysosome disruption, which in turn, reduces the activity of the inflammasome (By similarity). Interacts with RFTN1; the interaction occurs in response to lipopolysaccharide stimulation (PubMed:27022195). Interacts with SCIMP; the interaction occurs in response to lipopolysaccharide stimulation and is enhanced by phosphorylation of SCIMP by LYN (By similarity). This interaction facilitates the phosphorylation of TLR4 by LYN which elicits a selective cytokine response in macrophages (By similarity). Interacts with TRAF3IP3 (PubMed:30573680). Interacts with TREM1; this interaction enhances TLR4-mediated inflammatory response (PubMed:17098818, PubMed:21393102). Interacts with ZG16B/PAUF (PubMed:36232715). Interacts with CD82; this interaction inhibits TLR4-mediated signaling pathway (PubMed:36945827). Interacts with neutrophil recruitment protein from Aedes aegypti saliva; the interaction probably promotes activation of canonical NF-kappa-B signaling in skin-resident macrophages and subsequent expression of neutrophil chemoattractants (PubMed:38378891). Interacts with CD180; this interaction inhibits TLR4-mediated signaling pathway upon ligand binding (PubMed:15852007).SUBUNIT (Microbial infection) In case of infection, interacts with uropathogenic E.coli protein TcpC.SUBUNIT (Microbial infection) In case of infection, interacts with B.melitensis protein TcpB; TcpB abolishes the TLR4-TIRAP interaction in vitro.SUBUNIT (Microbial infection) Interacts with ebolavirus protein GP; this interaction leads to the production of proinflammatory cytokines and suppressor of cytokine signaling 1/SOCS1.INTERACTION Upon complex formation with CD36 and TLR6, internalized through dynamin-dependent endocytosis (PubMed:20037584). Colocalizes with RFTN1 at cell membrane and then together with RFTN1 moves to endosomes, upon lipopolysaccharide stimulation. Co-localizes with ZG16B/PAUF at the cell membrane of pancreatic cancer cells (PubMed:36232715).ALTERNATIVE PRODUCTS Highly expressed in placenta, spleen and peripheral blood leukocytes (PubMed:9237759, PubMed:9435236). Detected in monocytes, macrophages, dendritic cells and several types of T-cells (PubMed:27022195, PubMed:9237759). Expressed in pancreatic cancer cells but not in normal pancreatic cells (at protein level) (PubMed:36232715).INDUCTION By LPS in plasmacytoid dendritic cells.DOMAIN The TIR domain mediates interaction with NOX4.PTM N-Glycosylation of Asn-526 and Asn-575 by STT3A-containing OST-A complex is necessary for the expression of TLR4 on the cell surface and the LPS-response (PubMed:11706042, PubMed:38670073). Likewise, mutants lacking two or more of the other N-glycosylation sites were deficient in interaction with LPS (PubMed:11706042, PubMed:38670073).PTM Phosphorylated on tyrosine residues by LYN after binding lipopolysaccharide.PTM Ubiquitinated by RNF128 via 'Lys-28'-linked polyubiquitin chains, leading to proteasomal degradation.POLYMORPHISM Allele TLR4*B (Gly-299, Ile-399) is associated with a blunted response to inhaled LPS.MISCELLANEOUS His-456 and His-458 are found in TLR4 of human and several other primate species and may be responsible for inflammatory responses triggered by nickel (Ni(2+)). Ni(2+) may cross-link the two receptor monomers through specific histidines, triggering the formation of a dimer that structurally resembles that induced by LPS. This process may be the basis for the development of contact allergy to Ni(2+). A mouse model of contact allergy to Ni(2+) in which TLR4-deficient mice expresses human TLR4 has been proposed.SIMILARITY Belongs to the Toll-like receptor family.CAUTION In some plant proteins and in human SARM1, the TIR domain has NAD(+) hydrolase (NADase) activity (PubMed:28334607). However, despite the presence of the catalytic Asp residue, the isolated TIR domain of human TLR4 lacks NADase activity (PubMed:28334607). Based on this, it is unlikely that Toll-like receptors have NADase activity.ONLINE INFORMATION Zips, necklaces and mobile telephones - Issue 134 of December 2011 |
| description | recommendedName: Toll-like receptor 4 alternativeName: hToll cdAntigenNameCD284/cdAntigenName |
| geneName | TLR4 |
| identifier | O00206 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Age-related macular degeneration Alternative splicing Cell membrane Cell projection Direct protein sequencing Disulfide bond Endosome Glycoprotein Immunity Inflammatory response Innate immunity Leucine-rich repeat Membrane NAD Proteomics identification Receptor Reference proteome Repeat Signal Transmembrane Transmembrane helix Ubl conjugation |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9948485] Weiser, Joel, 2025-05-21 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20 |
| name | TLR4 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:9002691] ENSEMBL:ENSG00000136869 TLR4 [Homo sapiens] |
| secondaryIdentifier | TLR4_HUMAN A8K1Y8 A9XLP9 A9XLQ0 A9XLQ1 B4E194 D1CS52 D1CS53 Q5VZI8 Q5VZI9 Q9UK78 Q9UM57 |
| sequenceLength | 839 |
| species | [Species:48887] Homo sapiens |
| (isoformParent) | [ReferenceIsoform:386264] UniProt:O00206-2 TLR4 [Homo sapiens] [ReferenceIsoform:386265] UniProt:O00206-3 TLR4 [Homo sapiens] [ReferenceIsoform:401091] UniProt:O00206-1 TLR4 [Homo sapiens] |
| (referenceEntity) | [EntityWithAccessionedSequence:166045] 2xN4GlycoAsn-TLR4 [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:2201285] TLR4 [endosome membrane] [Homo sapiens] |
| (referenceSequence) | [ModifiedResidue:3322083] N4-glycosyl-L-asparagine at 526 [ModifiedResidue:3322088] N4-glycosyl-L-asparagine at 575 |
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No pathways have been reviewed or authored by UniProt:O00206 TLR4 (66107)
