Toll-like receptor 6 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''TLR6''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. TLR6 is a transmembrane protein, member of

toll-like receptor Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are Bitopic protein, single-pass membrane-spanning Receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophage ...

family, which belongs to the

pattern recognition receptor Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...

(PRR) family. TLR6 acts in a heterodimer form with

toll-like receptor 2 Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the ''TLR2'' gene. TLR2 has also been designated as CD282 (cluster of differentiation 282). TLR2 is one of the toll-like receptors and plays a role in the immune ...

(TLR2). Its ligands include multiple diacyl lipopeptides derived from

gram-positive bacteria In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...

and

mycoplasma ''Mycoplasma'' is a genus of bacteria that, like the other members of the class ''Mollicutes'', lack a cell wall around their cell membranes. Peptidoglycan (murein) is absent. This characteristic makes them naturally resistant to antibiotics ...

and several fungal cell wall saccharides. After dimerizing with TLR2, the

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

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 The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...

286).

Function

The protein encoded by this gene is a member of the

(TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from

Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...

to humans and share structural and functional similarities. They recognize

pathogen-associated molecular patterns Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. A vast arra ...

(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

(TLR2) to mediate cellular response to

fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...

, some

viruses A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...

and even

protozoa Protozoa (singular: protozoan or protozoon; alternative plural: protozoans) are a group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic tissues and debris. Histo ...

Interactions

TLR6 has been shown to interact in a heterodimer form with

TLR2 Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the ''TLR2'' gene. TLR2 has also been designated as CD282 (cluster of differentiation 282). TLR2 is one of the toll-like receptors and plays a role in the immune sys ...

. Synergistic interactions of TLR2/6 and

TLR9 Toll-like receptor 9 is a protein that in humans is encoded by the ''TLR9'' gene. TLR9 has also been designated as CD289 (cluster of differentiation 289). It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expresse ...

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 Lipoteichoic acid (LTA) is a major constituent of the cell wall of gram-positive bacteria. These organisms have an inner (or cytoplasmic) membrane and, external to it, a thick (up to 80 nanometer) peptidoglycan layer. The structure of LTA varies be ...

, found on the cell wall of

or macrophage-activating lipopeptide (MALP2), found on the cell membrane of

. It is also known that TLR2/6 binds some viral products, among them hepatitis C core and NS3 protein from the

hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, a ...

virus and glycoprotein B from

cytomegalovirus ''Cytomegalovirus'' (''CMV'') (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order ''Herpesvirales'', in the family ''Herpesviridae'', in the subfamily ''Betaherpe ...

. Several fungal ligands such as glucuronoxylomannan, phospholipomannan and

zymosan Zymosan is a glucan with repeating glucose units connected by β-1,3-glycosidic linkages. It binds to TLR 2 Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the ''TLR2'' gene. TLR2 has also been designated as CD ...

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 Nuclear may refer to: Physics Relating to the nucleus of the atom: *Nuclear engineering *Nuclear physics *Nuclear power *Nuclear reactor *Nuclear weapon *Nuclear medicine *Radiation therapy *Nuclear warfare Mathematics * Nuclear space *Nuclear ...

(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 Lactobacillales are an order of gram-positive, low-GC, acid-tolerant, generally nonsporulating, nonrespiring, either rod-shaped (bacilli) or spherical (cocci) bacteria that share common metabolic and physiological characteristics. These bacte ...

have been reported to stimulate immune regulation via TLR2/6, leading to tolerogenic

interleukin 10 Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti- inflammatory cytokine. In humans, interleukin 10 is encoded by the ''IL10'' gene. IL-10 signals through a receptor complex consisting of two IL-10 ...

secretion, instead of pro-inflammatory cytokine secretion.

Expression

In human, TLR6 is highly expressed in appendix,

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

and

lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...

. Among the immune cells, TLR6 has been detected in conventional

dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...

monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...

macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...

neutrophils Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

NK cells Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...

and

B lymphocytes B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

Clinical significance

A 359T>C

single-nucleotide polymorphism In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently lar ...

(SNP) in the extracellular leucine rich repeat domain is associated with susceptibility to

Legionnaires’ Disease Legionnaires' disease is a form of atypical pneumonia caused by any species of ''Legionella'' bacteria, quite often '' Legionella pneumophila''. Signs and symptoms include cough, shortness of breath, high fever, muscle pains, and headaches. Naus ...

. Increased occurrence of

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...

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.

References

External links

* * * * * {{TLR signaling pathway Clusters of differentiation 6