Toll (gene family)

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The toll genes encode members of the toll-like receptor class of proteins. Mutants in the toll gene were originally identified by 1995 Nobel Laureates Christiane Nüsslein-Volhard and Eric Wieschaus and colleagues in the fruit fly Drosophila melanogaster in 1985, [1] and cloned by the laboratory of Kathryn Anderson in 1988. [2] Since then, thirteen mammalian toll genes have been identified.

Toll-like receptor class of proteins that play a key role in the innate immune system

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, though the last three are not found in humans.

Christiane Nüsslein-Volhard German biologist

Christiane (Janni) Nüsslein-Volhard is a German developmental biologist and 1995 Nobel Prize-winner.

Drosophilidae taxonomic family of flies

The Drosophilidae are a diverse, cosmopolitan family of flies, which includes fruit flies. Another unrelated family of flies, Tephritidae, also includes species known as "small fruit flies". The best known species of the Drosophilidae is Drosophila melanogaster, within the genus Drosophila, and this species is used extensively for studies concerning genetics, development, physiology, ecology and behaviour. This fruit fly is mostly composed of post-mitotic cells, has a very short lifespan, and shows gradual aging. As in other species, temperature influences the life history of the animal. Several genes have been identified that can be manipulated to extend the lifespan of these insects.

Contents

In flies, toll was first identified as a gene important in embryogenesis in establishing the dorsal-ventral axis. In 1996, toll was found to have a role in the fly's immunity to fungal infections. [3] Both mammalian and invertebrate toll genes are required for innate immunity.

Fungus Any member of the eukaryotic kingdom that includes organisms such as yeasts, molds and mushrooms

A fungus 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, fungi, which is separate from the other eukaryotic life kingdoms of plants and animals.

Infection invasion of a host by disease-causing organisms

Infection is the invasion of an organism's body tissues by disease-causing agents, their multiplication, and the reaction of host tissues to the infectious agents and the toxins they produce. Infectious disease, also known as transmissible disease or communicable disease, is illness resulting from an infection.

Invertebrate Animals without a vertebrate column

Invertebrates are animals that neither possess nor develop a vertebral column, derived from the notochord. This includes all animals apart from the subphylum Vertebrata. Familiar examples of invertebrates include arthropods, mollusks, annelids, and cnidarians.

Toll-like receptors in mammals were identified in 1997 at Yale University by Ruslan Medzhitov and Charles Janeway. [4] Concurrently, two separate studies, led by Shizuo Akira, Bruce A. Beutler and their respective colleagues discovered that the Toll-like receptors (TLRs) act as the principal sensors of infection in mammals. [5] [6]

Yale University private research university in New Haven, Connecticut, United States

Yale University is an American private Ivy League research university in New Haven, Connecticut. Founded in 1701, it is the third-oldest institution of higher education in the United States and one of the nine Colonial Colleges chartered before the American Revolution.

Ruslan M. Medzhitov is a professor of immunobiology at Yale School of Medicine, a member of Yale Cancer Center, and a Howard Hughes Medical Institute investigator. His research focuses on the analysis of the innate immune system, inflammatory response, innate control of the adaptive immunity, and host-pathogen interactions.

Charles Alderson Janeway, Jr. (1943–2003) was a noted immunologist. A member of the National Academy of Sciences, he held a faculty position at Yale University's Medical School and was an HHMI Investigator.

The name of the gene family derives from Christiane Nüsslein-Volhard's 1985 exclamation, "Das ist ja toll!" [1] The exclamation, which translates as "That's amazing!" was in reference to the underdeveloped ventral portion of a fruit fly larva. The adjective "toll" is German for "amazing" or "great". [7]

German language West Germanic language

German is a West Germanic language that is mainly spoken in Central Europe. It is the most widely spoken and official or co-official language in Germany, Austria, Switzerland, South Tyrol (Italy), the German-speaking Community of Belgium, and Liechtenstein. It is also one of the three official languages of Luxembourg and a co-official language in the Opole Voivodeship in Poland. The languages which are most similar to German are the other members of the West Germanic language branch: Afrikaans, Dutch, English, the Frisian languages, Low German/Low Saxon, Luxembourgish, and Yiddish. There are also strong similarities in vocabulary with Danish, Norwegian and Swedish, although those belong to the North Germanic group. German is the second most widely spoken Germanic language, after English.

See also

Related Research Articles

Morphogen

A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various specialized cell types within a tissue. More specifically, a morphogen is a signaling molecule that acts directly on cells to produce specific cellular responses depending on its local concentration.

Lipid A chemical compound

Lipid A is a lipid component of an endotoxin held responsible for the toxicity of gram-negative bacteria. It is the innermost of the three regions of the lipopolysaccharide (LPS), also called endotoxin molecule, and its hydrophobic nature allows it to anchor the LPS to the outer membrane. While its toxic effects can be damaging, the sensing of lipid A by the human immune system may also be critical for the onset of immune responses to gram-negative infection, and for the subsequent successful fight against the infection.

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 the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

TLR3 protein-coding gene in the species Homo sapiens

Toll-like receptor 3 (TLR3) also known as CD283 is a protein that in humans is encoded by the TLR3 gene. TLR3 is a member of the toll-like receptor family of pattern recognition receptors of the innate immune system.

Gap gene Gene used to develop body sections in embryos

A gap gene is a type of gene involved in the development of the segmented embryos of some arthropods. Gap genes are defined by the effect of a mutation in that gene, which causes the loss of contiguous body segments, resembling a gap in the normal body plan. Each gap gene, therefore, is necessary for the development of a section of the organism.

TLR2 protein-coding gene in the species Homo sapiens

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. TLR2 is one of the toll-like receptors and plays a role in the immune system. TLR2 is a membrane protein, a receptor, which is expressed on the surface of certain cells and recognizes foreign substances and passes on appropriate signals to the cells of the immune system.

TLR 1 protein-coding gene in the species Homo sapiens

TLR 1 is a member of the toll-like receptor family (TLR) of pattern recognition receptors of the innate immune system. TLR1 recognizes pathogen-associated molecular pattern with a specificity for gram-positive bacteria. TLR1 has also been designated as CD281.

TIR-domain-containing adapter-inducing interferon-β (TRIF) is an adapter in responding to activation of toll-like receptors (TLRs). It mediates the rather delayed cascade of two TLR-associated signaling cascades, where the other one is dependent upon a MyD88 adapter.

TLR7 protein-coding gene in the species Homo sapiens

Toll-like receptor 7, also known as TLR7, is a protein that in humans is encoded by the TLR7 gene. Orthologs are found in mammals and birds. It is a member of the toll-like receptor (TLR) family and detects single stranded RNA.

TLR5 protein-coding gene in the species Homo sapiens

Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene. It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria. It has been shown to be involved in the onset of many diseases, which includes Inflammatory bowel disease. Recent studies have also shown that malfunctioning of TLR5 is likely related to osteoclastogenesis and bone loss. Abnormal TLR5 functioning is related to the onset of gastric, cervical, endometrial and ovarian cancers.

TLR4 protein-coding gene in the species Homo sapiens

Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an intracellular signaling pathway NF-κB and inflammatory cytokine production which is responsible for activating the innate immune system. It is most well-known for recognizing lipopolysaccharide (LPS), a component present in many Gram-negative bacteria and select Gram-positive bacteria. Its ligands also include several viral proteins, polysaccharide, and a variety of endogenous proteins such as low-density lipoprotein, beta-defensins, and heat shock protein.

Pair-rule gene

A pair-rule gene is a type of gene involved in the development of the segmented embryos of insects. Pair-rule genes are expressed as a result of differing concentrations of gap gene proteins, which encode transcription factors controlling pair-rule gene expression. Pair-rule genes are defined by the effect of a mutation in that gene, which causes the loss of the normal developmental pattern in alternating segments.

TLR6 protein-coding gene in the species Homo sapiens

Toll-like receptor 6 is a protein that in humans is encoded by the TLR6 gene. TLR6 has also been designated as CD286.

TLR10 protein-coding gene in the species Homo sapiens

Toll-like receptor 10 is a protein that in humans is encoded by the TLR10 gene. TLR10 has also been designated as CD290 . TLR10 has not been extensively studied because it is a pseudogene in mice, though all other mammalian species contain an intact copy of the TLR10 gene. Unlike other TLRs, TLR10 does not activate the immune system and has instead been shown to suppress inflammatory signaling on primary human cells. This makes TLR10 unique among the TLR family. No ligand is currently known for TLR10.

Bruce Beutler American immunologist and geneticist

Bruce Alan Beutler is an American immunologist and geneticist. Together with Jules A. Hoffmann, he received one-half of the 2011 Nobel Prize in Physiology or Medicine, for "their discoveries concerning the activation of innate immunity".

Jules A. Hoffmann French biologist

Jules A. Hoffmann is a Luxembourg-born French biologist. During his youth, growing up in Luxembourg, he developed a strong interest in insects under the influence of his father, Jos Hoffmann. This eventually resulted in the younger Hoffmann's dedication to the field of biology using insects as model organisms. He currently holds a faculty position at the University of Strasbourg. He is a research director and member of the board of administrators of the National Center of Scientific Research (CNRS) in Strasbourg, France. He was elected to the positions of Vice-President (2005-2006) and President (2007-2008) of the French Academy of Sciences. Hoffmann and Bruce Beutler were jointly awarded a half share of the 2011 Nobel Prize in Physiology or Medicine for "their discoveries concerning the activation of innate immunity,". [More specifically, the work showing increased Drosomycin expression following activation of Toll pathway in microbial infection.]

Patched (Ptc) is a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates. Patched is an essential gene in embryogenesis for proper segmentation in the fly embryo, mutations in which may be embryonic lethal. Patched functions as the receptor for the Hedgehog protein and controls its spatial distribution, in part via endocytosis of bound Hedgehog protein, which is then targeted for lysosomal degradation.

Toll-Interleukin receptor InterPro Domain

The Toll/interleukin-1 receptor (TIR) homology domain is an intracellular signaling domain found in MyD88, interleukin-1 receptors, Toll receptors and many plant R proteins. It contains three highly conserved regions, and mediates protein-protein interactions between the Toll-like receptors (TLRs) and signal-transduction components. TIR-like motifs are also found in plant proteins thought to be involved in resistance to disease. When activated, TIR domains recruit cytoplasmic adaptor proteins MyD88 and TOLLIP. In turn, these associate with various kinases to set off signaling cascades.

References

  1. 1 2 Hansson GK, Edfeldt K (2005). "Toll to be paid at the gateway to the vessel wall". Arterioscler. Thromb. Vasc. Biol. 25 (6): 1085–7. doi:10.1161/01.ATV.0000168894.43759.47. PMID   15923538.
  2. ↑ Hashimoto C, Hudson KL, Anderson KV (1988). "The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein". Cell. 52 (2): 269–79. doi:10.1016/0092-8674(88)90516-8. PMID   2449285.
  3. ↑ Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA (1996). "The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults". Cell. 86 (6): 973–983. doi:10.1016/S0092-8674(00)80172-5. PMID   8808632.
  4. ↑ Medzhitov R, Preston-Hurlburt P, Janeway CA (1997). "A human homologue of the Drosophila Toll protein signals activation of adaptive immunity". Nature. 388 (6640): 394–7. doi:10.1038/41131. PMID   9237759.
  5. ↑ Hoshino, K; Takeuchi, O; Kawai, T; Sanjo, H; Ogawa, T; Takeda, Y; Takeda, K; Akira, S (Apr 1, 1999). "Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product". Journal of Immunology. 162 (7): 3749–52. PMID   10201887.
  6. ↑ Poltorak, Alexander; et al. (1998). "Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene". Science . 282 (5396): 2085–2088. doi:10.1126/science.282.5396.2085. PMID   9851930.
  7. ↑ "toll - LEO Deutsch-English Worterbuch" . Retrieved 2011-10-03.

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