Toll-like receptor 3 (TLR3) also known as CD283 (

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 ...

283) 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, res ...

that in humans is encoded by the ''TLR3''

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 b ...

. TLR3 is a member of the

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

family of

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 ...

s of the innate immune system. TLR3 recognizes double-stranded RNA in

endosomes Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane ca ...

, which is a common feature of viral

genomes In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...

internalised by

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 ...

and dendritic cells.

Function

TLR3 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

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

s necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...

and

pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an en ...

, and is restricted to the

dendritic Dendrite derives from the Greek word "dendron" meaning ( "tree-like"), and may refer to: Biology *Dendrite, a branched projection of a neuron *Dendrite (non-neuronal), branching projections of certain skin cells and immune cells Physical * Dendr ...

subpopulation of the leukocytes. It recognizes

dsRNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

associated with viral infection, and induces the activation of

IRF3 Interferon regulatory factor 3, also known as IRF3, is an interferon regulatory factor. Function IRF3 is a member of the interferon regulatory transcription factor (IRF) family. IRF3 was originally discovered as a homolog of IRF1 and IRF2. ...

and

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 ...

. Unlike other TLRs, TLR3 uses TRIF as the sole adaptor.

ultimately induces the production of type I interferons. It may thus play a role in host defense against viruses. TLR3 recognizes double-stranded RNA, a form of genetic information carried by some

virus 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 Ivanovsk ...

es such as

reovirus ''Reoviridae'' is a family of double-stranded RNA viruses. Member viruses have a wide host range, including vertebrates, invertebrates, plants, protists and fungi. They lack lipid envelopes and package their segmented genome within multi-layered ...

es. Additionally, an ephemeral form of double-stranded RNA exists as a replicative intermediate during virus replication. Upon recognition, TLR 3 induces the activation of

to increase production of type I interferons which signal other cells to increase their antiviral defenses.

Double-stranded RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydr ...

is also recognised by the cytoplasmic receptors

RIG-I RIG-I (retinoic acid-inducible gene I) is a cytosolic pattern recognition receptor (PRR) responsible for the type-1 interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that have been infect ...

and MDA-5. TLR3 displays a protective role in mouse models of

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...

, and activation of TLR3 signaling is associated with ischemic preconditioning-induced protection against brain ischemia and attenuation of reactive astrogliosis. Furthermore, TLR3 activation has been shown to promote hair follicle regeneration in skin wound healing. In addition, TLR3 activators show effects on human vascular cells.

Structure

The structure of TLR3 was reported in June 2005 by researchers at The Scripps Research Institute. TLR3 forms a large horseshoe shape that contacts with a neighboring horseshoe, forming a "dimer" of two horseshoes. Much of the TLR3 protein surface is covered with sugar molecules, making it a glycoprotein, but on one face (including the proposed interface between the two horseshoes), there is a large sugar-free surface. This surface also contains two distinct patches rich in positively charged amino acids, which may be a binding site for negatively charged double-stranded RNA. Despite being a glycoprotein, TLR3 crystallises readily – a prerequisite for structural analysis by

x-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...

Ligands

; Antagonists *

CU-CPT4a CU-CPT4a is a drug which acts as a selective antagonist of Toll-like receptor 3 (TLR3), with an IC50 of 3.44 μM. It is used for research into the function of TRL3 and its role in inflammation, autoimmune disorders and cancer. See also * CU-CP ...

Function

Structure

Ligands

References

Further reading