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    TLR4 toll like receptor 4 [ Homo sapiens (human) ]

    Gene ID: 7099, updated on 10-Dec-2024

    Summary

    Official Symbol
    TLR4provided by HGNC
    Official Full Name
    toll like receptor 4provided by HGNC
    Primary source
    HGNC:HGNC:11850
    See related
    Ensembl:ENSG00000136869 MIM:603030; AllianceGenome:HGNC:11850
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    TOLL; CD284; TLR-4; ARMD10
    Summary
    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. In silico studies have found a particularly strong binding of surface TLR4 with the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease-2019 (COVID-19). This receptor has also 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, and with susceptibility to age-related macular degeneration. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2020]
    Annotation information
    Note: This gene has been reviewed for its involvement in coronavirus biology, and is relevant for COVID-19 treatment.
    Expression
    Broad expression in spleen (RPKM 17.1), appendix (RPKM 15.6) and 22 other tissues See more
    Orthologs
    NEW
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    Try the new Transcript table

    Genomic context

    See TLR4 in Genome Data Viewer
    Location:
    9q33.1
    Exon count:
    4
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 9 NC_000009.12 (117704403..117724735)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 9 NC_060933.1 (129898286..129918621)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 9 NC_000009.11 (120466681..120487013)

    Chromosome 9 - NC_000009.12Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC101928797 Neighboring gene NANOG hESC enhancer GRCh37_chr9:120449653-120450182 Neighboring gene ribosomal protein L35a pseudogene 22 Neighboring gene CDK7 strongly-dependent group 2 enhancer GRCh37_chr9:120466103-120467302 Neighboring gene CDK7 strongly-dependent group 2 enhancer GRCh37_chr9:120467367-120468566 Neighboring gene RNA, U6 small nuclear 1082, pseudogene Neighboring gene uncharacterized LOC105376244 Neighboring gene P300/CBP strongly-dependent group 1 enhancer GRCh37_chr9:120525140-120526339 Neighboring gene uncharacterized LOC105376243 Neighboring gene uncharacterized LOC105376246

    Genomic regions, transcripts, and products

    Expression

    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?

    Phenotypes

    BioGRID CRISPR Screen Phenotypes (9 hits/1257 screens)

    EBI GWAS Catalog

    Description
    Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium.
    EBI GWAS Catalog
    Meta-analysis identifies loci affecting levels of the potential osteoarthritis biomarkers sCOMP and uCTX-II with genome wide significance.
    EBI GWAS Catalog
    Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population.
    EBI GWAS Catalog

    HIV-1 interactions

    Protein interactions

    Protein Gene Interaction Pubs
    Envelope surface glycoprotein gp120 env HIV-1 CN54, JRFL, and Ada Env (gp120) upregulates IL-6, CCL2, CCL4, CXCL8, and IL-1b through TLR4 and CCR5 induction in monocyte derived macrophages and hepatic stellate cells because treatment with an anti-TLR4 antibody mitigated the response PubMed
    env The binding of soluble HIV-1 gp120 to TLR2 or TLR4 results in upregulation of the TNF-alpha and IL-8 production through NF-kappaB activation PubMed
    env Human primary astrocytes exposed to HIV-1 gp120 has a significant increase in TLR4 protein expression PubMed
    Tat tat HIV-1 Tat engages TLR4, which induces production of TNF and IL10 in human monocytes PubMed
    tat HIV-1 Tat downregulates TLR4 by specific dynamin endocytosis as a result of Tat-TLR4 interaction PubMed
    tat HIV-1 Tat engages TLR4 resulting in RELA (NK-kappaB) activation and IL6 and CXCL8 (IL8) protein expression PubMed
    tat HIV-1 Tat-induced release of TNF-alpha and IL-10 is TLR4-dependent in monocytes PubMed
    tat HIV-1 Tat-mediated regulation of MSRV and Syncytin-1 involves TLR-4 in primary astrocytes PubMed
    tat HIV-1 Tat upregulates the expression of CCR2, CD16, and TLR4 in monocyte-derived macrophages PubMed
    tat HIV-1 Tat interacts physically with the TLR4-MD2 complex and the N-terminal region (residues 1-29) of Tat is involved in the interation with TLR4-MD2 PubMed
    tat HIV-1 Tat-induced upregulation of PD-L1 on monocyte-derived dendritic cells involves a TNF-alpha-mediated mechanism through the TLR4 pathway PubMed
    tat HIV-1 Tat protein decreases TLR4 protein levels and suppresses C. parvum-induced TLR4 protein expression PubMed
    Vpr vpr HIV-1 Vpr-induced IL-6 production depends on the activation of NFkappaB and the involvement of C/EBP-beta, TLR4, and MyD88 PubMed
    vpr HIV-1 Vpr potentiates the suppression of Toll-like receptor 4 by glucocorticoids via the glucocorticoid receptor pathway PubMed

    Go to the HIV-1, Human Interaction Database

    Pathways from PubChem

    Interactions

    General gene information

    Gene Ontology Provided by GOA

    Items 1 - 25 of 109
    Process Evidence Code Pubs
    involved_in B cell proliferation involved in immune response  
    involved_in ERK1 and ERK2 cascade  
    involved_in I-kappaB phosphorylation PubMed 
    involved_in JNK cascade  
    involved_in MHC class II biosynthetic process  
    involved_in MyD88-dependent toll-like receptor signaling pathway  
    involved_in MyD88-dependent toll-like receptor signaling pathway PubMed 
    involved_in MyD88-dependent toll-like receptor signaling pathway  
    involved_in T-helper 1 type immune response PubMed 
    involved_in TRIF-dependent toll-like receptor signaling pathway  
    involved_in astrocyte development  
    involved_in cellular response to amyloid-beta PubMed 
    involved_in cellular response to amyloid-beta PubMed 
    involved_in cellular response to lipopolysaccharide PubMed 
    involved_in cellular response to lipopolysaccharide PubMed 
    involved_in cellular response to lipopolysaccharide  
    involved_in cellular response to lipoteichoic acid  
    involved_in cellular response to mechanical stimulus PubMed 
    involved_in cellular response to oxidised low-density lipoprotein particle stimulus PubMed 
    involved_in cellular response to oxidised low-density lipoprotein particle stimulus  
    involved_in cellular response to platelet-derived growth factor stimulus  
    involved_in cellular response to type II interferon PubMed 
    involved_in defense response to Gram-negative bacterium  
    involved_in defense response to Gram-negative bacterium PubMed 
    involved_in defense response to bacterium PubMed 
    involved_in defense response to bacterium PubMed 
    involved_in detection of fungus PubMed 
    involved_in detection of lipopolysaccharide  
    involved_in detection of lipopolysaccharide PubMed 
    involved_in gene expression  
    involved_in immune response PubMed 
    involved_in inflammatory response  
    involved_in innate immune response PubMed 
    involved_in innate immune response PubMed 
    involved_in intestinal epithelial structure maintenance  
    NOT acts_upstream_of_or_within lipopolysaccharide-mediated signaling pathway PubMed 
    acts_upstream_of_or_within lipopolysaccharide-mediated signaling pathway PubMed 
    involved_in macrophage activation PubMed 
    involved_in microglia differentiation  
    involved_in negative regulation of ERK1 and ERK2 cascade  
    involved_in negative regulation of cold-induced thermogenesis PubMed 
    involved_in negative regulation of interleukin-17 production  
    involved_in negative regulation of interleukin-23 production  
    involved_in negative regulation of interleukin-6 production  
    involved_in negative regulation of osteoclast differentiation PubMed 
    involved_in negative regulation of tumor necrosis factor production  
    involved_in negative regulation of type II interferon production  
    involved_in nitric oxide biosynthetic process  
    involved_in nitric oxide production involved in inflammatory response  
    involved_in nucleotide-binding oligomerization domain containing 1 signaling pathway  
    involved_in nucleotide-binding oligomerization domain containing 2 signaling pathway  
    involved_in phagocytosis PubMed 
    involved_in positive regulation of B cell proliferation  
    involved_in positive regulation of ERK1 and ERK2 cascade  
    involved_in positive regulation of JNK cascade  
    acts_upstream_of positive regulation of MAP kinase activity  
    involved_in positive regulation of MHC class II biosynthetic process  
    acts_upstream_of_or_within positive regulation of NF-kappaB transcription factor activity PubMed 
    involved_in positive regulation of NF-kappaB transcription factor activity PubMed 
    acts_upstream_of positive regulation of NF-kappaB transcription factor activity PubMed 
    involved_in positive regulation of NLRP3 inflammasome complex assembly  
    involved_in positive regulation of canonical NF-kappaB signal transduction PubMed 
    involved_in positive regulation of cellular response to macrophage colony-stimulating factor stimulus PubMed 
    involved_in positive regulation of chemokine (C-X-C motif) ligand 2 production PubMed 
    involved_in positive regulation of chemokine production PubMed 
    involved_in positive regulation of cytokine production involved in inflammatory response PubMed 
    involved_in positive regulation of cytokine production involved in inflammatory response  
    involved_in positive regulation of extrinsic apoptotic signaling pathway  
    involved_in positive regulation of gene expression PubMed 
    involved_in positive regulation of gene expression  
    involved_in positive regulation of inflammatory response PubMed 
    involved_in positive regulation of inflammatory response PubMed 
    involved_in positive regulation of interferon-alpha production  
    involved_in positive regulation of interferon-beta production  
    involved_in positive regulation of interleukin-1 beta production PubMed 
    involved_in positive regulation of interleukin-1 beta production  
    involved_in positive regulation of interleukin-1 production  
    involved_in positive regulation of interleukin-10 production  
    involved_in positive regulation of interleukin-12 production PubMed 
    involved_in positive regulation of interleukin-12 production  
    involved_in positive regulation of interleukin-6 production PubMed 
    involved_in positive regulation of interleukin-6 production PubMed 
    involved_in positive regulation of interleukin-8 production PubMed 
    involved_in positive regulation of macrophage activation  
    involved_in positive regulation of macrophage cytokine production  
    involved_in positive regulation of matrix metallopeptidase secretion PubMed 
    involved_in positive regulation of nitric oxide biosynthetic process  
    involved_in positive regulation of non-canonical NF-kappaB signal transduction PubMed 
    involved_in positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway  
    involved_in positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway  
    involved_in positive regulation of platelet activation PubMed 
    involved_in positive regulation of reactive oxygen species biosynthetic process  
    involved_in positive regulation of smooth muscle cell migration  
    involved_in positive regulation of smooth muscle cell proliferation  
    involved_in positive regulation of stress-activated MAPK cascade  
    involved_in positive regulation of transcription by RNA polymerase II  
    involved_in positive regulation of tumor necrosis factor production PubMed 
    involved_in positive regulation of tumor necrosis factor production PubMed 
    involved_in positive regulation of tumor necrosis factor production  
    involved_in positive regulation of type II interferon production  
    involved_in regulation of dendritic cell cytokine production  
    involved_in response to lipopolysaccharide PubMed 
    acts_upstream_of_or_within response to lipopolysaccharide PubMed 
    involved_in response to lipopolysaccharide PubMed 
    involved_in stress-activated MAPK cascade  
    involved_in toll-like receptor 4 signaling pathway  
    involved_in toll-like receptor 4 signaling pathway PubMed 
    involved_in toll-like receptor signaling pathway PubMed 
    involved_in wound healing involved in inflammatory response  
    Items 1 - 25 of 109
    Component Evidence Code Pubs
    located_in cell surface PubMed 
    located_in cytoplasm PubMed 
    located_in cytoplasm PubMed 
    located_in early endosome  
    is_active_in endosome membrane PubMed 
    located_in endosome membrane  
    located_in external side of plasma membrane PubMed 
    part_of lipopolysaccharide receptor complex  
    part_of lipopolysaccharide receptor complex PubMed 
    located_in perinuclear region of cytoplasm PubMed 
    located_in phagocytic cup PubMed 
    is_active_in plasma membrane  
    is_active_in plasma membrane PubMed 
    located_in plasma membrane PubMed 
    located_in plasma membrane  
    located_in plasma membrane PubMed 
    located_in plasma membrane  
    part_of receptor complex PubMed 
    located_in ruffle  

    General protein information

    Preferred Names
    toll-like receptor 4
    Names
    hToll
    homolog of Drosophila toll
    toll like receptor 4 protein
    NP_003257.1
    NP_612564.1
    NP_612567.1

    NCBI Reference Sequences (RefSeq)

    NEW Try the new Transcript table

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_011475.2 RefSeqGene

      Range
      5001..25333
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_320

    mRNA and Protein(s)

    1. NM_003266.4 → NP_003257.1  toll-like receptor 4 isoform C

      See identical proteins and their annotated locations for NP_003257.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) contains an additional internal exon compared to transcript variant 1. This variant represents translation initiation at a downstream AUG compared to variant 1; the 5'-most initiation codon, as used in variant 1, is associated with a weak Kozak sequence and a truncated ORF that would render the transcript a candidate for nonsense-mediated decay (NMD). Leaky scanning may allow translation initiation at the downstream AUG, which results in an isoform (C) with a shorter N-terminus compared to isoform A.
      Source sequence(s)
      AK226155, AL160272, BC025294, BC143841, BG622357, DA187988, DA218006
      UniProtKB/TrEMBL
      D1CS55
      Related
      ENSP00000377997.4, ENST00000394487.5
      Conserved Domains (6) summary
      smart00082
      Location:539 → 585
      LRRCT; Leucine rich repeat C-terminal domain
      smart00255
      Location:634 → 775
      TIR; Toll - interleukin 1 - resistance
      cd00116
      Location:112 → 416
      LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
      sd00031
      Location:16 → 39
      LRR_1; leucine-rich repeat [structural motif]
      sd00033
      Location:335 → 360
      LRR_RI; leucine-rich repeat [structural motif]
      pfam13855
      Location:17 → 74
      LRR_8; Leucine rich repeat
    2. NM_138554.5 → NP_612564.1  toll-like receptor 4 isoform A precursor

      See identical proteins and their annotated locations for NP_612564.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes the longest isoform (A).
      Source sequence(s)
      AK226155, AL160272, BC117422, BG622357, DA187988, DA218006
      Consensus CDS
      CCDS6818.1
      UniProtKB/Swiss-Prot
      A8K1Y8, A9XLP9, A9XLQ0, A9XLQ1, B4E194, D1CS52, D1CS53, O00206, Q5VZI8, Q5VZI9, Q9UK78, Q9UM57
      UniProtKB/TrEMBL
      D1CS55
      Related
      ENSP00000363089.5, ENST00000355622.8
      Conserved Domains (6) summary
      smart00082
      Location:579 → 625
      LRRCT; Leucine rich repeat C-terminal domain
      smart00255
      Location:674 → 815
      TIR; Toll - interleukin 1 - resistance
      cd00116
      Location:152 → 456
      LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
      sd00031
      Location:56 → 79
      LRR_1; leucine-rich repeat [structural motif]
      sd00033
      Location:353 → 374
      LRR_RI; leucine-rich repeat [structural motif]
      pfam13855
      Location:57 → 114
      LRR_8; Leucine rich repeat
    3. NM_138557.3 → NP_612567.1  toll-like receptor 4 isoform D

      See identical proteins and their annotated locations for NP_612567.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (4) lacks an internal exon compared to transcript variant 1. This variant represents translation initiation at a downstream AUG compared to variant 1; the 5'-most initiation codon, as used in variant 1, is associated with a weak Kozak sequence and a truncated ORF that would render the transcript a candidate for nonsense-mediated decay (NMD). Leaky scanning may allow translation initiation at the downstream AUG, which results in an isoform (D) with a shorter N-terminus compared to isoform A.
      Source sequence(s)
      AK226155, AL160272, BC025294, BG622357, DA218006
      UniProtKB/Swiss-Prot
      O00206
      Conserved Domains (5) summary
      smart00082
      Location:379 → 425
      LRRCT; Leucine rich repeat C-terminal domain
      smart00255
      Location:474 → 615
      TIR; Toll - interleukin 1 - resistance
      cd00116
      Location:27 → 256
      LRR_RI; Leucine-rich repeats (LRRs), ribonuclease inhibitor (RI)-like subfamily. LRRs are 20-29 residue sequence motifs present in many proteins that participate in protein-protein interactions and have different functions and cellular locations. LRRs correspond ...
      sd00033
      Location:175 → 200
      LRR_RI; leucine-rich repeat [structural motif]
      pfam13855
      Location:247 → 308
      LRR_8; Leucine rich repeat

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000009.12 Reference GRCh38.p14 Primary Assembly

      Range
      117704403..117724735
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060933.1 Alternate T2T-CHM13v2.0

      Range
      129898286..129918621
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

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