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

Gene ID: 7099, updated on 24-Nov-2020

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
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

Genomic context

See TLR4 in Genome Data Viewer
Location:
9q33.1
Exon count:
4
Annotation release Status Assembly Chr Location
109.20201120 current GRCh38.p13 (GCF_000001405.39) 9 NC_000009.12 (117704403..117724735)
105 previous assembly GRCh37.p13 (GCF_000001405.25) 9 NC_000009.11 (120466453..120479769)

Chromosome 9 - NC_000009.12Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC101928797 Neighboring gene ribosomal protein L35a pseudogene 22 Neighboring gene RNA, U6 small nuclear 1082, pseudogene Neighboring gene uncharacterized LOC105376244 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

Associated conditions

Description Tests
Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium.
GeneReviews: Not available
Meta-analysis identifies loci affecting levels of the potential osteoarthritis biomarkers sCOMP and uCTX-II with genome wide significance.
GeneReviews: Not available
Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population.
GeneReviews: Not available

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

Products Interactant Other Gene Complex Source Pubs Description

General gene information

Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
NAD(P)+ nucleosidase activity IEA
Inferred from Electronic Annotation
more info
 
NAD+ nucleotidase, cyclic ADP-ribose generating IEA
Inferred from Electronic Annotation
more info
 
amyloid-beta binding IC
Inferred by Curator
more info
PubMed 
identical protein binding IPI
Inferred from Physical Interaction
more info
PubMed 
lipopolysaccharide binding IBA
Inferred from Biological aspect of Ancestor
more info
PubMed 
lipopolysaccharide binding IMP
Inferred from Mutant Phenotype
more info
PubMed 
lipopolysaccharide binding NAS
Non-traceable Author Statement
more info
PubMed 
lipopolysaccharide immune receptor activity IBA
Inferred from Biological aspect of Ancestor
more info
PubMed 
lipopolysaccharide immune receptor activity IDA
Inferred from Direct Assay
more info
PubMed 
protein binding IPI
Inferred from Physical Interaction
more info
PubMed 
protein heterodimerization activity IPI
Inferred from Physical Interaction
more info
PubMed 
signaling receptor activity IBA
Inferred from Biological aspect of Ancestor
more info
PubMed 
signaling receptor binding IPI
Inferred from Physical Interaction
more info
PubMed 
transmembrane signaling receptor activity NAS
Non-traceable Author Statement
more info
PubMed 
Process Evidence Code Pubs
B cell proliferation involved in immune response IEA
Inferred from Electronic Annotation
more info
 
I-kappaB kinase/NF-kappaB signaling TAS
Traceable Author Statement
more info
 
I-kappaB phosphorylation IDA
Inferred from Direct Assay
more info
PubMed 
MyD88-dependent toll-like receptor signaling pathway ISS
Inferred from Sequence or Structural Similarity
more info
 
MyD88-dependent toll-like receptor signaling pathway TAS
Traceable Author Statement
more info
 
MyD88-independent toll-like receptor signaling pathway TAS
Traceable Author Statement
more info
 
T-helper 1 type immune response NAS
Non-traceable Author Statement
more info
PubMed 
TRIF-dependent toll-like receptor signaling pathway ISS
Inferred from Sequence or Structural Similarity
more info
 
TRIF-dependent toll-like receptor signaling pathway TAS
Traceable Author Statement
more info
 
activation of MAPK activity ISS
Inferred from Sequence or Structural Similarity
more info
 
activation of innate immune response IEA
Inferred from Electronic Annotation
more info
 
apoptotic signaling pathway TAS
Traceable Author Statement
more info
 
astrocyte development IEA
Inferred from Electronic Annotation
more info
 
cellular response to amyloid-beta IGI
Inferred from Genetic Interaction
more info
PubMed 
cellular response to interferon-gamma IDA
Inferred from Direct Assay
more info
PubMed 
cellular response to lipopolysaccharide IDA
Inferred from Direct Assay
more info
PubMed 
cellular response to lipopolysaccharide IGI
Inferred from Genetic Interaction
more info
PubMed 
cellular response to lipopolysaccharide ISS
Inferred from Sequence or Structural Similarity
more info
 
cellular response to lipoteichoic acid IEA
Inferred from Electronic Annotation
more info
 
cellular response to mechanical stimulus IEP
Inferred from Expression Pattern
more info
PubMed 
cellular response to oxidised low-density lipoprotein particle stimulus ISS
Inferred from Sequence or Structural Similarity
more info
 
defense response to Gram-negative bacterium IBA
Inferred from Biological aspect of Ancestor
more info
PubMed 
defense response to Gram-negative bacterium IC
Inferred by Curator
more info
PubMed 
defense response to bacterium IGI
Inferred from Genetic Interaction
more info
PubMed 
defense response to bacterium TAS
Traceable Author Statement
more info
PubMed 
detection of fungus NAS
Non-traceable Author Statement
more info
PubMed 
detection of lipopolysaccharide IDA
Inferred from Direct Assay
more info
PubMed 
immune response TAS
Traceable Author Statement
more info
PubMed 
inflammatory response IBA
Inferred from Biological aspect of Ancestor
more info
PubMed 
innate immune response TAS
Traceable Author Statement
more info
PubMed 
interferon-gamma production IEA
Inferred from Electronic Annotation
more info
 
interleukin-1 beta production ISS
Inferred from Sequence or Structural Similarity
more info
 
intestinal epithelial structure maintenance ISS
Inferred from Sequence or Structural Similarity
more info
 
NOT lipopolysaccharide-mediated signaling pathway IDA
Inferred from Direct Assay
more info
PubMed 
lipopolysaccharide-mediated signaling pathway IGI
Inferred from Genetic Interaction
more info
PubMed 
macrophage activation IMP
Inferred from Mutant Phenotype
more info
PubMed 
necroptotic process TAS
Traceable Author Statement
more info
 
negative regulation of ERK1 and ERK2 cascade ISS
Inferred from Sequence or Structural Similarity
more info
 
negative regulation of MyD88-independent toll-like receptor signaling pathway TAS
Traceable Author Statement
more info
 
negative regulation of cold-induced thermogenesis ISS
Inferred from Sequence or Structural Similarity
more info
PubMed 
negative regulation of interferon-gamma production ISS
Inferred from Sequence or Structural Similarity
more info
 
negative regulation of interleukin-17 production ISS
Inferred from Sequence or Structural Similarity
more info
 
negative regulation of interleukin-23 production ISS
Inferred from Sequence or Structural Similarity
more info
 
negative regulation of interleukin-6 production ISS
Inferred from Sequence or Structural Similarity
more info
 
negative regulation of osteoclast differentiation NAS
Non-traceable Author Statement
more info
PubMed 
negative regulation of tumor necrosis factor production ISS
Inferred from Sequence or Structural Similarity
more info
 
nitric oxide production involved in inflammatory response IEA
Inferred from Electronic Annotation
more info
 
phagocytosis IDA
Inferred from Direct Assay
more info
PubMed 
positive regulation of B cell proliferation IEA
Inferred from Electronic Annotation
more info
 
positive regulation of ERK1 and ERK2 cascade IEA
Inferred from Electronic Annotation
more info
 
positive regulation of I-kappaB kinase/NF-kappaB signaling IEA
Inferred from Electronic Annotation
more info
 
positive regulation of JNK cascade IEA
Inferred from Electronic Annotation
more info
 
positive regulation of MHC class II biosynthetic process IEA
Inferred from Electronic Annotation
more info
 
positive regulation of NF-kappaB transcription factor activity IDA
Inferred from Direct Assay
more info
PubMed 
positive regulation of NF-kappaB transcription factor activity IGI
Inferred from Genetic Interaction
more info
PubMed 
positive regulation of NIK/NF-kappaB signaling IDA
Inferred from Direct Assay
more info
PubMed 
positive regulation of NLRP3 inflammasome complex assembly ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of cellular response to macrophage colony-stimulating factor stimulus IDA
Inferred from Direct Assay
more info
PubMed 
positive regulation of chemokine (C-X-C motif) ligand 2 production IMP
Inferred from Mutant Phenotype
more info
PubMed 
positive regulation of chemokine production IDA
Inferred from Direct Assay
more info
PubMed 
positive regulation of cytokine production involved in inflammatory response IMP
Inferred from Mutant Phenotype
more info
PubMed 
positive regulation of cytokine production involved in inflammatory response ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of gene expression IMP
Inferred from Mutant Phenotype
more info
PubMed 
positive regulation of gene expression ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of inflammatory response IC
Inferred by Curator
more info
PubMed 
positive regulation of inflammatory response IMP
Inferred from Mutant Phenotype
more info
PubMed 
positive regulation of interferon-alpha production ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of interferon-beta production ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of interferon-gamma production ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of interleukin-1 beta production IDA
Inferred from Direct Assay
more info
PubMed 
positive regulation of interleukin-1 production ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of interleukin-10 production ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of interleukin-12 production IDA
Inferred from Direct Assay
more info
PubMed 
positive regulation of interleukin-12 production ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of interleukin-6 production IDA
Inferred from Direct Assay
more info
PubMed 
positive regulation of interleukin-6 production IMP
Inferred from Mutant Phenotype
more info
PubMed 
positive regulation of interleukin-8 production IDA
Inferred from Direct Assay
more info
PubMed 
positive regulation of keratinocyte proliferation IDA
Inferred from Direct Assay
more info
PubMed 
positive regulation of macrophage activation ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of macrophage cytokine production IEA
Inferred from Electronic Annotation
more info
 
positive regulation of matrix metallopeptidase secretion IMP
Inferred from Mutant Phenotype
more info
PubMed 
positive regulation of nitric oxide biosynthetic process ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of nitric-oxide synthase biosynthetic process ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway IEA
Inferred from Electronic Annotation
more info
 
positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway IEA
Inferred from Electronic Annotation
more info
 
positive regulation of oxidative stress-induced neuron death ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of platelet activation ISS
Inferred from Sequence or Structural Similarity
more info
PubMed 
positive regulation of reactive oxygen species biosynthetic process ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of transcription by RNA polymerase II ISS
Inferred from Sequence or Structural Similarity
more info
 
positive regulation of tumor necrosis factor production IDA
Inferred from Direct Assay
more info
PubMed 
positive regulation of tumor necrosis factor production IMP
Inferred from Mutant Phenotype
more info
PubMed 
positive regulation of tumor necrosis factor production ISS
Inferred from Sequence or Structural Similarity
more info
 
regulation of dendritic cell cytokine production IEA
Inferred from Electronic Annotation
more info
 
response to lipopolysaccharide IC
Inferred by Curator
more info
PubMed 
response to lipopolysaccharide IDA
Inferred from Direct Assay
more info
PubMed 
toll-like receptor 4 signaling pathway TAS
Traceable Author Statement
more info
 
toll-like receptor signaling pathway IBA
Inferred from Biological aspect of Ancestor
more info
PubMed 
toll-like receptor signaling pathway TAS
Traceable Author Statement
more info
 
Component Evidence Code Pubs
Golgi apparatus IDA
Inferred from Direct Assay
more info
 
cell surface IDA
Inferred from Direct Assay
more info
PubMed 
cytoplasm IDA
Inferred from Direct Assay
more info
PubMed 
cytoplasm IPI
Inferred from Physical Interaction
more info
PubMed 
early endosome IEA
Inferred from Electronic Annotation
more info
 
endosome membrane TAS
Traceable Author Statement
more info
 
external side of plasma membrane IDA
Inferred from Direct Assay
more info
PubMed 
integral component of plasma membrane IBA
Inferred from Biological aspect of Ancestor
more info
PubMed 
integral component of plasma membrane IDA
Inferred from Direct Assay
more info
PubMed 
intrinsic component of plasma membrane IDA
Inferred from Direct Assay
more info
PubMed 
lipopolysaccharide receptor complex IDA
Inferred from Direct Assay
more info
PubMed 
perinuclear region of cytoplasm IDA
Inferred from Direct Assay
more info
PubMed 
phagocytic cup IDA
Inferred from Direct Assay
more info
PubMed 
plasma membrane IDA
Inferred from Direct Assay
more info
PubMed 
plasma membrane ISS
Inferred from Sequence or Structural Similarity
more info
 
plasma membrane TAS
Traceable Author Statement
more info
 
receptor complex IPI
Inferred from Physical Interaction
more info
PubMed 
ruffle IEA
Inferred from Electronic Annotation
more info
 

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)

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)

mRNA and Protein(s)

  1. NM_003266.4NP_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/Swiss-Prot
    O00206
    Related
    ENSP00000377997.4, ENST00000394487.5
    Conserved Domains (6) summary
    smart00082
    Location:539585
    LRRCT; Leucine rich repeat C-terminal domain
    smart00255
    Location:634775
    TIR; Toll - interleukin 1 - resistance
    cd00116
    Location:112416
    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:1639
    LRR_1; leucine-rich repeat [structural motif]
    sd00033
    Location:335360
    LRR_RI; leucine-rich repeat [structural motif]
    pfam13855
    Location:1774
    LRR_8; Leucine rich repeat
  2. NM_138554.5NP_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
    O00206
    Related
    ENSP00000363089.5, ENST00000355622.8
    Conserved Domains (6) summary
    smart00082
    Location:579625
    LRRCT; Leucine rich repeat C-terminal domain
    smart00255
    Location:674815
    TIR; Toll - interleukin 1 - resistance
    cd00116
    Location:152456
    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:5679
    LRR_1; leucine-rich repeat [structural motif]
    sd00033
    Location:353374
    LRR_RI; leucine-rich repeat [structural motif]
    pfam13855
    Location:57114
    LRR_8; Leucine rich repeat
  3. NM_138557.3NP_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:379425
    LRRCT; Leucine rich repeat C-terminal domain
    smart00255
    Location:474615
    TIR; Toll - interleukin 1 - resistance
    cd00116
    Location:27256
    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:175200
    LRR_RI; leucine-rich repeat [structural motif]
    pfam13855
    Location:247308
    LRR_8; Leucine rich repeat

RefSeqs of Annotated Genomes: Homo sapiens Updated Annotation Release 109.20201120

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

Reference GRCh38.p13 Primary Assembly

Genomic

  1. NC_000009.12 Reference GRCh38.p13 Primary Assembly

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

Suppressed Reference Sequence(s)

The following Reference Sequences have been suppressed. Explain

  1. NM_138556.1: Suppressed sequence

    Description
    NM_138556.1: This RefSeq was permanently suppressed because currently there is insufficient support for the transcript and the protein is not supported by current protein homology data.
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