Toll-like receptor 6

Toll-like receptor 6 is a protein that in humans is encoded by the TLR6 gene. TLR6 is a transmembrane protein, member of toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. TLR6 acts in a heterodimer form with toll-like receptor 2 (TLR2). Its ligands include multiple diacyl lipopeptides derived from gram-positive bacteria and mycoplasma and several fungal cell wall saccharides. After dimerizing with TLR2, the NF-κB intracellular signalling pathway is activated, leading to a pro-inflammatory cytokine production and activation of innate immune response. TLR6 has also been designated as CD286 (cluster of differentiation 286).

TLR6
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4OM7
Identifiers
Aliases	TLR6, CD286, toll like receptor 6
External IDs	OMIM: 605403; MGI: 1341296; HomoloGene: 21223; GeneCards: TLR6; OMA:TLR6 - orthologs
Gene location (Human) Chr. Chromosome 4 (human) Band 4p14 Start 38,822,897 bp End 38,856,817 bp
Gene location (Mouse) Chr. Chromosome 5 (mouse) Band 5 C3.1|5 33.54 cM Start 65,109,374 bp End 65,117,440 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte blood lymph node granulocyte spleen appendix bone marrow cells Achilles tendon tonsil gallbladder Top expressed in granulocyte embryo blood stroma of bone marrow spleen muscle of thigh thymus calvaria carotid body tibiofemoral joint More reference expression data BioGPS More reference expression data
Gene ontology Molecular function Toll-like receptor 2 binding protein binding transmembrane signaling receptor activity lipopeptide binding amyloid-beta binding signaling receptor binding signaling receptor activity identical protein binding protein heterodimerization activity Cellular component integral component of membrane phagocytic vesicle membrane membrane integral component of plasma membrane cytoplasmic vesicle Golgi apparatus membrane raft Toll-like receptor 2-Toll-like receptor 6 protein complex plasma membrane intracellular anatomical structure receptor complex Biological process positive regulation of NLRP3 inflammasome complex assembly immune system process positive regulation of JUN kinase activity cellular response to diacyl bacterial lipopeptide activation of NF-kappaB-inducing kinase activity toll-like receptor 6 signaling pathway defense response to bacterium positive regulation of I-kappaB kinase/NF-kappaB signaling inflammatory response toll-like receptor TLR6:TLR2 signaling pathway detection of diacyl bacterial lipopeptide signal transduction innate immune response T-helper 1 type immune response MyD88-dependent toll-like receptor signaling pathway nitric oxide metabolic process response to bacterial lipoprotein microglial cell activation toll-like receptor signaling pathway cell activation immune response positive regulation of gene expression negative regulation of toll-like receptor 2 signaling pathway TRIF-dependent toll-like receptor signaling pathway positive regulation of macrophage activation positive regulation of nitric oxide biosynthetic process positive regulation of NF-kappaB transcription factor activity cellular response to oxidised low-density lipoprotein particle stimulus positive regulation of cytokine production involved in inflammatory response positive regulation of oxidative stress-induced neuron death positive regulation of reactive oxygen species biosynthetic process cellular response to amyloid-beta Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10333 21899 Ensembl ENSG00000174130 ENSMUSG00000051498 UniProt Q9Y2C9 Q9EPW9 RefSeq (mRNA) NM_006068 NM_001394553 NM_011604 NM_001359180 NM_001384171 RefSeq (protein) NP_006059 NP_035734 NP_001346109 NP_001371100 Location (UCSC) Chr 4: 38.82 – 38.86 Mb Chr 5: 65.11 – 65.12 Mb PubMed search
Wikidata
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Function

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 (PAMPs) 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 functionally interacts with toll-like receptor 2 (TLR2) to mediate cellular response to gram-positive bacteria, mycoplasma, fungi, some viruses and even protozoa.

Interactions

TLR6 has been shown to interact in a heterodimer form with TLR2. Synergistic interactions of TLR2/6 and TLR9 leading to higher resistance against lung infection have also been reported.

Agonists

Unlike TLR2/1 heterodimer, which recognizes triacylated lipopeptides, the TLR2/6 heterodimer is known to be specific for diacylated lipopeptides such as lipoteichoic acid, found on the cell wall of gram-positive bacteria or macrophage-activating lipopeptide (MALP2), found on the cell membrane of mycoplasma. It is also known that TLR2/6 binds some viral products, among them hepatitis C core and NS3 protein from the hepatitis C virus and glycoprotein B from cytomegalovirus. Several fungal ligands such as glucuronoxylomannan, phospholipomannan and zymosan have been reported. Moreover, TLR2/6 is known to bind one protozoan ligand – lipopeptidophosphoglycan. TLR2/6 can also be activated by synthetic lipopeptides, such as Pam₂CSK₄ or Fibroblast–stimulating lipopeptide (FSL-1).

Signalling

After ligand recognition, TLR6 receptor dimerizes with TLR2. Ligand-mediated dimerization is crucial for recruiting the adaptor proteins, which are necessary for transmitting the signal inside the cell. TLR2/6 heterodimer, just as most of the Toll-like receptors, generally induces MyD88-dependent intracellular signalling pathway, which leads to nuclear translocation of nuclear factor-κB (NF-κB), resulting in the production of pro-inflammatory cytokines. But MyD88 also activates mitogen‐activated protein kinases (MAPKs). However, several strains of lactic acid bacteria have been reported to stimulate immune regulation via TLR2/6, leading to tolerogenic interleukin 10 secretion, instead of pro-inflammatory cytokine secretion.

Expression

In human, TLR6 is highly expressed in appendix, spleen and lymph node. Among the immune cells, TLR6 has been detected in conventional dendritic cells, monocytes, macrophages, microglia, neutrophils, NK cells and B lymphocytes.

Clinical significance

A 359T>C single-nucleotide polymorphism (SNP) in the extracellular leucine rich repeat domain is associated with susceptibility to Legionnaires’ Disease. Increased occurrence of asthma in some populations may be associated with Ser249Pro polymorphism, also present in the extracellular domain of the encoded protein. On the other hand, a protective SNP also exists - S249P is possibly liked to protection from bronchial asthma and resistance from asthma in children.

Further reading

• Lien E, Ingalls RR (January 2002). "Toll-like receptors". Critical Care Medicine. 30 (1 Suppl): S1-11. doi:10.1097/00003246-200201001-00001. PMID 11782555.

External links

• Toll-Like Receptor 6 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• TLR6 human gene location in the UCSC Genome Browser.
• TLR6 human gene details in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: Q9Y2C9 (Human Toll-like receptor 6) at the PDBe-KB.
• Overview of all the structural information available in the PDB for UniProt: Q9EPW9 (Mouse Toll-like receptor 6) at the PDBe-KB.