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FLASH GENE
Symbol TLR4 contributors: mct/pgu/shn - updated : 18-02-2016
HGNC name toll-like receptor 4
HGNC id 11850
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a 23 amino acids signal peptide (2.4 kDa)
  • 22 extracellular leucine-rich repeats (LRRs),
  • a transmembrane domain,
  • the Toll/IL-1 receptor domain (TIR domain) that is essential for TLR signaling and conserved among members of the Toll receptor family
  • a cysteine rich region
  • a cytoplasmic domain
  • conjugated GlycoP
    mono polymer complex
    isoforms Precursor an 816 amino acids mature protein (93.3 kDa)
    HOMOLOGY
    interspecies ortholog to TLR4, Pan troglodytes
    ortholog to Tlr4, Rattus norvegicus
    ortholog to Tlr4, Mus musculus
    intraspecies homolog to CD180
    Homologene
    FAMILY
  • Toll-like receptor family
  • CATEGORY immunity/defense , receptor membrane
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,Golgi
    intracellular,nuclear envelope
    text
  • localized in the plasma membrane and the Golgi apparatus, where it colocalizes with TICAM2
  • at the plasma membrane, TLR4 engages with MYD88 and signals to activate NFKB
  • basic FUNCTION
  • pathogen associated molecular pattern (PAMP) recognition and activation of innate immunity and mediating the production of cytokines and the inflammatory response
  • microglial protein playing a critical role in chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptor (downregulation of ADRBK1, and GPRK5)
  • playing a role in innate immunity and in the etiology of neuropathic pain
  • may be the major, and possibly the exclusive, receptor for LPS isolated from most gram-negative organisms
  • multifunctional molecule participating in photoreceptor outer segment membrane recognition, oxidant production, LPS recognition, and cytokine production
  • is essential for recognizing a Gram-negative bacterial component, lipopolysaccharide (LPS)
  • master regulator of inflammatory muscle catabolism
  • involved in modulating innate immunity, and is an important mediator of insulin resistance
  • contributes to the development of insulin resistance and inflammation through its activation by elevated exogenous ligands
  • signaling by innate immune receptors such as TLR4 and NLRP3 regulate metabolism
  • activation of mitochondrial oxidative stress in photoreceptor
  • key role for TLR4 in mediating HSPA14 interaction with dendritic cells
  • insufficiency of chaperone expression links TLR4 signaling to endoplasmic reticulum stress
  • TLR4 may play a much more important role in early-onset preeclampsia (PE)
  • crucial and innate role of TLR4 in promoting the activation of CD4+ and gammadelta T cells, which contributes to the initiation of autoimmune inflammation
  • TLR4 regulates intestinal stem cells (ISCs) proliferation and apoptosis
  • TLR4 activation on the intestinal stem cells can increase apoptosis and reduce proliferation
  • important contribution of TLR4-mediated microglial activation by endogenous photoreceptor proteins in retinal inflammation that aggravates retinal cell death
  • can recognize endogenous products as their ligands, and play an important role in pathogenesis of degenerative neural diseases, especially in the retina
  • cell surface TLR4 and extrinsically secreted LY96 are capable of forming the functional complex extracellularly, indicating an additional or alternative pathway for the complex formation
  • TLR4 mediates host responses to pathogens through a mechanism that involves protein myeloid differentiation-2 (LY96) and its soluble form sLY96
  • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS immunity/defense
    text
  • endotoxin sensor, apoptosis of infected cells
  • activation of adaptive immunity (
  • innate and allergic immune responses (
  • PATHWAY
    metabolism
    signaling signal transduction
  • signal transduction pathway induced by liposaccharide (LPS) found in most Gram(-) bacteria receptor
  • TLR4 signaling in CD4+ T cells acts to enhance activation in the absence of TcR stimulation and promote survival
  • a component
  • component of a complex (LPS receptor) with LY96 and CD14 involved in the rapid traffic of LPS from Golgi to plasma membrane
  • leucine at position 815 is required for the normal maturation of TLR4 and for formation of the TLR4.LY96 complex
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • binding CD14 required for LPS recognition
  • binding directly to TLR2
  • binding MYD88 and TIRAP via their TIR domain
  • toll interacting protein, TOLLIP (
  • Gp96 (
  • myeloid differentiation protein-2, MD-2 (
  • beta-defensin 2, mDF2beta (
  • Bruton's tyrosine kinase, Btk (
  • toll-like receptor 5, TLR5 (
  • JNK-interacting protein 3, JIP3 (
  • TICAM-1 and TICAM-2 (
  • spleen tyrosine kinase, SYK (
  • NAD(P)H oxidase 4 isozyme (
  • receptor-interacting protein 2, RIP2 (
  • High mobility group box 1, HMGB1 (
  • PRotein Associated with Tlr4, PRAT4B (
  • Myeloid Differentiation primary response protein 88, MyD88 (
  • S1PR1 or S1PR3
  • lipopolysaccharide, LPS (
  • TLR4 requires myeloid differentiation (LY96), and both TLR2 and TLR4 signal need myeloid differentiation factor (MYD88)
  • FOXO1
  • PRDX1
  • KCNJ3
  • is one of the most important functional receptors mediating biological activities of HSPA14
  • LY96 binds LPS with high affinity and is critical for TLR4-dependent signal transduction
  • insufficient LPS-induced chaperone expression links TLR4 signaling to endoplasmic reticulum stress
  • LPS induced the increased physical association of TLR4 with HSP90B1 but not with HSPA5
  • CNPY4 positively regulates TLR4 surface expression but plays a negatively regulatory role in the surface expression of TLR1
  • TLR4 is expressed on the LGR5-positive intestinal stem cells
  • BBC3 mediates the increased apoptosis and reduced proliferation within intestinal crypts that is induced by TLR4
  • LRRFIP2 is involved in NFKB1 activation following stimulation of TLR4
  • IL10 activates TLR4 and requires MYD88 for cardiomyocyte survival
  • not only TLR4 signaling, but also CD180 appears to be an essential accessory for immune responses through TLR2 signaling
  • by inhibiting the degradation of TRAF3 during TLR4 activation, USP25 enables a balanced innate immune response
  • LY96 is essential for lipopolysaccharide (LPS) recognition of Toll-like receptor 4 (TLR4) but not for cell surface expression
  • SIK1 and SIK3 negatively regulate TLR4-mediated signaling through the interruption of TAB2-TRAF6 complex and thereby the inhibition of ubiquitination of TRAF6
  • PRSS8 releases the ectodomain of TLR4 by cleaving it, which results in a reduction in the full-length form and reduces the activation of TLR4
  • TNFAIP8L2 can regulate TLR4 inflammatory effect and inhibit further amplification of cascade reaction via CASP8
  • CD14 is an endogenous ligand for CD33 and ligation of CD33 with CD14 modulates with the presentation of LPS from CD14 to TLR4, leading to down-regulation of TLR4-mediated signaling
  • TLR4-mediated expression of ITGAM in monocytes plays a pivotal role on monocyte adhesion to vascular endothelium, leading to increased foam cell formation in the development of atherosclerosis
  • HMGN1 is a potent alarmin that binds TLR4 and induces antigen-specific Th1 immune responses
  • SLC16A4 is required for macrophage activation upon TLR2 and TLR4 stimulations
  • TLR4 adaptor, myeloid differentiation factor 2 (LY96), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms
  • THBD promotes diabetic wound healing by regulating TLR4 expression
  • WDFY1 is a crucial adaptor protein in the TLR3/4 signaling pathway
  • WDFY1 recruits the signaling adaptor TICAM1 to TLR3 and TLR4, thereby potentiating signaling from these pattern recognition receptors (PRRs)
  • ANPEP negatively regulates TLR4 signaling, thereby balancing the innate response by maintaining the inflammatory equilibrium critical to innate immune regulation
  • TLR4 recruits TICAM2 as a sorting adaptor to facilitate the interaction between TLR4 and TICAM1 and then initiate TICAM1-dependent IRF3 activation
  • HAVCR2-signaling inhibited phosphorylation of IRF3, a TLR4 downstream transcriptional factor regulating macrophage polarization
  • MAP2K1 is required for TLR4 mediated ERK activation and in turn regulates the production of IL10 and IL12A
  • TRIM38 negatively regulates TLR3/4-mediated innate immune and inflammatory responses by two sequential and distinct mechanisms
  • TICAM2 bridges TLR4 and TICAM1 for LPS signaling in the endosome
  • HSPD1 is involved in the stimulation of VSMC migration, via TLR4 and ERK MAPK activation
  • important distinction between the TICAM1-mediated signaling pathways of TLR4 and TLR3
  • ANXA2 directly exerted negative regulation of inflammatory responses through TLR4-initiated TICAM2-TICAM1 pathway occurring on endosomes
  • PRG4 binds to TLR2 and TLR4 and this binding mediates a novel anti-inflammatory role for PRG4
  • SYK negatively regulates TLR4-mediated production of IFNB1 and IL10 and promotes inflammatory responses in dendritic cells through divergent regulation of downstream PI3K-AKT1 and NFKB1 signaling pathways
  • CD14 is a co-receptor of TLR4 in the S100A9-induced cytokine response
  • critical role of SPI1 in the regulation of TLR1, 2, 4 and of CD14
  • CSF3 downregulates TLR1, TLR2 and TLR4 in a time- and dose-dependent fashion in human monocytes
  • critical role of TOLLIP in the early phase of TLR4-mediated neuroinflammation
  • E3 ubiquitin ligase ZNRF1 modulates CAV1 protein stability to regulate Toll-like receptor (TLR) 4-triggered immune responses
  • CAMP selectively modulated synthesis of TLR4 and TLR9 in intestinal epithelium, but only when cells were exposed to virulence factors, mostly from apical surfaces
  • CD180 is implicated in the pathological process of multiple cardiovascular diseases through its functional and physical interactions with Toll&
  • 8209;like receptor 4 (TLR4)
  • CD180 ameliorates hypoxia&
  • 824;reoxygenation injury in cardiac microvascular endothelial cells by suppressing TLR4&
    824;MAPKs&
    824;NFKB1 signaling
    cell & other
    REGULATION
    activated by heme
    fibrinogen (activates TLR4, explaining how fibrinogen promotes inflammatory protein expression)
    inhibited by TLR1 in endothelial cells
    Other expression modulated by macrophage migration inhibitory factor MIF
    repressed in alveolar macrophages following inflammatory stimuli
    may be regulated by ATF3
    TLR4 activation in CD4+ T cells enhances proliferation and survival of CD4+ T cells
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    in adrenocortical carcinoma
    tumoral     --over  
    of TLR4 and MYD88 is associated with liver metastasis and is an independent predictor of poor prognosis in patients with colorectal cancer
    tumoral     --other  
    expressed in ovarian tumor cells specifically of granulosa cell origin
    constitutional     --over  
    in neonatal Gram-negative (G-) bacteremia
    tumoral     --over  
    CD74, MIF and TLR4 were found to be expressed in gastric cancer and increased significantly in the advanced stage, and were also associated with lymph node metastasis
    constitutional     --low  
    significantly lower in Relapsing Remitting Multiple Sclerosis (RRMS) patients than healthy controls
    constitutional       gain of function
    lead to the development of necrotizing enterocolitis (NEC), a devastating disease of the premature intestine
    Susceptibility
  • to severe sepsis following burn injury
  • resistance to legionnaire disease
  • to age-related macular dystrophy
  • Variant & Polymorphism SNP
  • SNP associated with severe sepsis following burn injury
  • SNP A896G or C1196T associated with resistance to legionnaire disease
  • D299G variant increasing the risk of age-related macular dystrophy
  • Candidate gene to new therapies for the prevention and treatment of neuropathic pain syndromes
    Marker
    Therapy target
  • reintroduction of TLR4 expression in adrenocortical carcinoma may provide a novel therapeutic strategy for adrenal cancer
  • ANIMAL & CELL MODELS
  • respiratory syncytial virus persisted longer in the lungs of infected TLR4-deficient mice (
  • TLR4-defective mice subjected to sensitization and pulmonary challenge with a protein allergen had reductions in airway inflammation with eosinophils, allergen-specific IgE levels, and Th2 cytokine production (
  • TLR4 deficiency of bone marrow-derived mast cells in mice resulted in significantly higher mortality because of defective neutrophil recruitment and production of proinflammatory cytokines in the peritoneal cavity (
  • TLR4(+/+) mice receiving TLR4(-/-) bone marrow, 6 weeks after transplant TLR4 was absent in all circulating leukocytes and in resident macrophages , and these cells were completely nonresponsive to lipopolysaccharide
  • TLR4(-/-) mice receiving TLR4(+/+) bone marrow, endothelial cells but not leukocytes were deficient in TLR4, numbers of circulating leukocytes decreased by 90%, and systemic LPS (0.5 mg/kg) induced a dramatic increase in neutrophil sequestration into the lungs (
  • Apolipoprotein E-deficient mice that also lacked TLR4 or MyD88 demonstrated reduced aortic atherosclerosis that was associated with reductions in circulating levels of proinflammatory cytokines IL-12 or monocyte chemoattractant protein 1, plaque lipid content, numbers of macrophage, and cyclooxygenase 2 immunoreactivity in their plaques (