TLR4
The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor has been implicated in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]
Function
Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195).
Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634, PubMed:27022195,PubMed:21393102).
Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni2+. Responses triggered by Ni2+ require non-conserved histidines and are, therefore, species-specific (PubMed:20711192).
Both M.tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa-B expression (PubMed:15809303).
In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. Binds electronegative LDL (LDL-) and mediates the cytokine release induced by LDL- (PubMed:23880187).
Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via TLR2, but also partially via this receptor (PubMed:16622205, PubMed:10835634, PubMed:15809303, PubMed:17478729, PubMed:20037584, PubMed:20711192, PubMed:23880187, PubMed:27022195, PubMed:9237759).
Activated by the signaling pathway regulator NMI which acts as damage-associated molecular patterns (DAMPs) in response to cell injury or pathogen invasion, therefore promoting nuclear factor NF-kappa-B activation (PubMed:29038465).
Biological Process
Biological Process activation of innate immune responseSource:Ensembl
Biological Process astrocyte developmentSource:Ensembl
Biological Process B cell proliferation involved in immune responseSource:Ensembl
Biological Process cellular response to amyloid-betaSource:ComplexPortal1 Publication
Biological Process cellular response to interferon-gammaSource:UniProtKB1 Publication
Biological Process cellular response to lipopolysaccharideSource:UniProtKB1 Publication
Biological Process cellular response to lipoteichoic acidSource:Ensembl
Biological Process cellular response to mechanical stimulusSource:UniProtKB1 Publication
Biological Process cellular response to oxidised low-density lipoprotein particle stimulusSource:ComplexPortal1 Publication
Biological Process cellular response to platelet-derived growth factor stimulusSource:Ensembl
Biological Process defense response to bacteriumSource:ARUK-UCL1 Publication
Biological Process defense response to Gram-negative bacteriumSource:GO_Central1 Publication
Biological Process detection of fungusSource:UniProtKB1 Publication
Biological Process detection of lipopolysaccharideSource:UniProtKB1 Publication
Biological Process ERK1 and ERK2 cascadeSource:Ensembl
Biological Process I-kappaB phosphorylationSource:BHF-UCL1 Publication
Biological Process immune responseSource:ProtInc1 Publication
Biological Process inflammatory responseSource:GO_Central1 Publication
Biological Process innate immune responseSource:BHF-UCL1 Publication
Biological Process intestinal epithelial structure maintenanceSource:BHF-UCL
Biological Process JNK cascadeSource:Ensembl
Biological Process lipopolysaccharide-mediated signaling pathwaySource:MGI2 Publications
Biological Process macrophage activationSource:UniProtKB1 Publication
Biological Process MHC class II biosynthetic processSource:Ensembl
Biological Process MyD88-dependent toll-like receptor signaling pathwaySource:ComplexPortal1 Publication
Biological Process negative regulation of cold-induced thermogenesisSource:YuBioLabBy Similarity
Biological Process negative regulation of ERK1 and ERK2 cascadeSource:BHF-UCL
Biological Process negative regulation of interferon-gamma productionSource:BHF-UCL
Biological Process negative regulation of interleukin-17 productionSource:BHF-UCL
Biological Process negative regulation of interleukin-23 productionSource:BHF-UCL
Biological Process negative regulation of interleukin-6 productionSource:BHF-UCL
Biological Process negative regulation of osteoclast differentiationSource:UniProtKB1 Publication
Biological Process negative regulation of tumor necrosis factor productionSource:BHF-UCL
Biological Process nitric oxide biosynthetic processSource:Ensembl
Biological Process nitric oxide production involved in inflammatory responseSource:Ensembl
Biological Process nucleotide-binding oligomerization domain containing 1 signaling pathwaySource:Ensembl
Biological Process nucleotide-binding oligomerization domain containing 2 signaling pathwaySource:Ensembl
Biological Process phagocytosisSource:UniProtKB1 Publication
Biological Process positive regulation of B cell proliferationSource:Ensembl
Biological Process positive regulation of cellular response to macrophage colony-stimulating factor stimulusSource:UniProtKB1 Publication
Biological Process positive regulation of chemokine (C-X-C motif) ligand 2 productionSource:ARUK-UCL1 Publication
Biological Process positive regulation of chemokine productionSource:BHF-UCL1 Publication
Biological Process positive regulation of cytokine production involved in inflammatory responseSource:ARUK-UCL1 Publication
Biological Process positive regulation of ERK1 and ERK2 cascadeSource:Ensembl
Biological Process positive regulation of gene expressionSource:UniProtKB1 Publication
Biological Process positive regulation of I-kappaB kinase/NF-kappaB signalingSource:Ensembl
Biological Process positive regulation of inflammatory responseSource:ARUK-UCL1 Publication
Biological Process positive regulation of interferon-alpha productionSource:BHF-UCL
Biological Process positive regulation of interferon-beta productionSource:BHF-UCL
Biological Process positive regulation of interferon-gamma productionSource:BHF-UCL
Biological Process positive regulation of interleukin-1 beta productionSource:UniProtKB1 Publication
Biological Process positive regulation of interleukin-1 productionSource:BHF-UCL
Biological Process positive regulation of interleukin-10 productionSource:BHF-UCL
Biological Process positive regulation of interleukin-12 productionSource:UniProtKB1 Publication
Biological Process positive regulation of interleukin-6 productionSource:BHF-UCL1 Publication
Biological Process positive regulation of interleukin-8 productionSource:UniProtKB1 Publication
Biological Process positive regulation of JNK cascadeSource:Ensembl
Biological Process positive regulation of macrophage activationSource:ARUK-UCL
Biological Process positive regulation of macrophage cytokine productionSource:Ensembl
Biological Process positive regulation of MAP kinase activitySource:BHF-UCL
Biological Process positive regulation of matrix metallopeptidase secretionSource:ARUK-UCL1 Publication
Biological Process positive regulation of MHC class II biosynthetic processSource:Ensembl
Biological Process positive regulation of NF-kappaB transcription factor activitySource:UniProtKB1 Publication
Biological Process positive regulation of NIK/NF-kappaB signalingSource:BHF-UCL1 Publication
Biological Process positive regulation of nitric oxide biosynthetic processSource:ARUK-UCL
Biological Process positive regulation of nitric-oxide synthase biosynthetic processSource:BHF-UCL
Biological Process positive regulation of NLRP3 inflammasome complex assemblySource:UniProtKB
Biological Process positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathwaySource:Ensembl
Biological Process positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathwaySource:Ensembl
Biological Process positive regulation of oxidative stress-induced neuron deathSource:ARUK-UCL
Biological Process positive regulation of platelet activationSource:BHF-UCLBy Similarity
Biological Process positive regulation of reactive oxygen species biosynthetic processSource:ARUK-UCL
Biological Process positive regulation of smooth muscle cell migrationSource:Ensembl
Biological Process positive regulation of smooth muscle cell proliferationSource:Ensembl
Biological Process positive regulation of transcription by RNA polymerase IISource:BHF-UCL
Biological Process positive regulation of tumor necrosis factor productionSource:UniProtKB1 Publication
Biological Process regulation of dendritic cell cytokine productionSource:Ensembl
Biological Process response to lipopolysaccharideSource:MGI2 Publications
Biological Process T-helper 1 type immune responseSource:UniProtKB1 Publication
Biological Process toll-like receptor 4 signaling pathwaySource:Ensembl
Biological Process toll-like receptor signaling pathwaySource:ComplexPortal1 Publication
Biological Process TRIF-dependent toll-like receptor signaling pathwaySource:ARUK-UCL
Biological Process wound healing involved in inflammatory responseSource:Ensembl
Cellular Location
Cell membrane
Early endosome
Cell projection, ruffle
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
PTM
N-glycosylated. Glycosylation of Asn-526 and Asn-575 seems to be necessary for the expression of TLR4 on the cell surface and the LPS-response. Likewise, mutants lacking two or more of the other N-glycosylation sites were deficient in interaction with LPS.
Phosphorylated on tyrosine residues by LYN after binding lipopolysaccharide.
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Datasheet