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 immunophe ...

283) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

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

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. 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 protein, single-spanning receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophages ...

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 th ...

s of the

innate immune system The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates (the other being the adaptive immune system). The innate immune system is an alternate defense strategy and is the dominant immune s ...

. TLR3 recognizes double-stranded

RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...

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

, which is a common feature of viral

genomes 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 genes, other functional regions of the genome such as ...

internalised by

macrophages Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

and

dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...

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 Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes, but not present in the host. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both p ...

) 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 produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

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 (: placentas or placentae) 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 ...

and

pancreas The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...

, 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 *Dendri ...

subpopulation of the

leukocyte White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

s. It recognizes

dsRNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself ( non-coding RNA) or by forming a template for the production of proteins ( messenger RNA). RNA and deoxy ...

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. IR ...

and

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...

. Unlike other TLRs, TLR3 uses TRIF as the sole adaptor. IRF3 ultimately induces the production of type I

interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten ...

s. It may thus play a role in host defense against viruses. TLR3 recognizes double-stranded

, a form of genetic information carried by some

virus A virus is a submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are ...

es such as

reovirus ''Sedoreoviridae'' (''sedo'' = smooth) is a family of the ''Reovirales'' order of viruses. Viruses in this family are distinguished by the absence of a turreted protein on the inner capsid to produce a smooth surface. Taxonomy The family contain ...

es. Additionally, an ephemeral form of double-stranded RNA exists as a replicative intermediate during virus replication. Upon recognition, TLR3 induces the activation of IRF3 to increase production of type I interferons which signal other cells to increase their antiviral defenses.

Double-stranded RNA Double-stranded RNA (dsRNA) is RNA with two complementary strands found in cells. It is similar to DNA but with the replacement of thymine by uracil and the adding of one oxygen atom. Despite the structural similarities, much less is known about ...

is also recognised by the cytoplasmic receptors

RIG-I RIG-I (retinoic acid-inducible gene I) is a cytosolic pattern recognition receptor (PRR) that can mediate induction of a type-I interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that ...

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

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...

, 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 Scripps Research is a nonprofit American medical research facility that focuses on research and education in the biomedical sciences. Headquartered in San Diego, California, the institute has over 170 laboratories employing 2,100 scientists, tec ...

. 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 Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecul ...

molecules, making it a

glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...

, 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 Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

, which may be a binding site for negatively charged double-stranded RNA. Despite being a

, TLR3 crystallises readily – a prerequisite for structural analysis by

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

Ligands

; Antagonists * CU-CPT4a

Function

Structure

Ligands

References

Further reading