Lymphocyte antigen 96, also known as "Myeloid Differentiation factor 2 (MD-2)," is a protein that in humans is encoded by the LY96 gene. [5] [6] [7] [8]
The protein encoded by this gene is involved in binding lipopolysaccharide with Toll-Like Receptor (TLR4).
The MD-2 protein appears to associate with toll-like receptor 4 on the cell surface and confers responsiveness to lipopolysaccharide (LPS), thus providing a link between the receptor and LPS signaling. [7] That is, the primary interface between TLR4 and MD-2 is formed before binding LPS and the dimerization interface is induced by binding LPS. [8]
MD-2 has a β-cup fold structure composed of two anti-parallel β sheets forming a large hydrophobic pocket for ligand binding. [9] [10]
Lymphocyte antigen 96 has been shown to interact with TLR 4. [5] [11]
When LPS binds to a hydrophobic pocket in MD-2, it directly mediates dimerization of the two TLR4-MD-2 complexes. Thus, TLR4 and MD-2 form a heterodimer that recognizes a common pattern in structurally diverse LPS molecules. These interactions allow TLR4 to recognize LPS. [8] Macrophages in MD-2 knockout mice are unresponsive to LPS. [12]
LPS is extracted from the bacterial membrane and transferred to TLR4-MD-2 by two accessory proteins, LPS-binding protein and CD14, to induce innate immune response. [8]
Lipopolysaccharide, now more commonly known as endotoxin, is a collective term for components of the outermost membrane of cell envelope of gram-negative bacteria, such as E. coli and Salmonella with a common structural architecture. Lipopolysaccharides (LPS) are large molecules consisting of three parts: an outer core polysaccharide termed the O-antigen, an inner core oligosaccharide and Lipid A, all covalently linked. In current terminology, the term endotoxin is often used synonymously with LPS, although there are a few endotoxins that are not related to LPS, such as the so-called delta endotoxin proteins produced by Bacillus thuringiensis.
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-spanning 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. Humans lack genes for TLR11, TLR12 and TLR13 and mice lack a functional gene for TLR10. The receptors TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the cell membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles.
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 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.
CD14 is a human protein made mostly by macrophages as part of the innate immune system. It helps to detect bacteria in the body by binding lipopolysaccharide (LPS), a pathogen-associated molecular pattern (PAMP).
Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the MYD88 gene. originally discovered in the laboratory of Dan A. Liebermann as a Myeloid differentiation primary response gene.
Lipoarabinomannan, also called LAM, is a glycolipid, and a virulence factor associated with Mycobacterium tuberculosis, the bacteria responsible for tuberculosis. Its primary function is to inactivate macrophages and scavenge oxidative radicals.
Depyrogenation refers to the removal of pyrogens from solutions, most commonly from injectable pharmaceuticals.
Collectins (collagen-containing C-type lectins) are a part of the innate immune system. They form a family of collagenous Ca2+-dependent defense lectins, which are found in animals. Collectins are soluble pattern recognition receptors (PRRs). Their function is to bind to oligosaccharide structure or lipids that are on the surface of microorganisms. Like other PRRs they bind pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) of oligosaccharide origin. Binding of collectins to microorganisms may trigger elimination of microorganisms by aggregation, complement activation, opsonization, activation of phagocytosis, or inhibition of microbial growth. Other functions of collectins are modulation of inflammatory, allergic responses, adaptive immune system and clearance of apoptotic cells.
Lipopolysaccharide binding protein (LBP) is a protein that in humans is encoded by the LBP gene.
Toll-like receptor 4 (TLR4), also designated as CD284, is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approximately 95 kDa that is encoded by the TLR4 gene.
High mobility group box 1 protein, also known as high-mobility group protein 1 (HMG-1) and amphoterin, is a protein that in humans is encoded by the HMGB1 gene.
Interleukin-1 receptor-associated kinase 1 (IRAK-1) is an enzyme in humans encoded by the IRAK1 gene. IRAK-1 plays an important role in the regulation of the expression of inflammatory genes by immune cells, such as monocytes and macrophages, which in turn help the immune system in eliminating bacteria, viruses, and other pathogens. IRAK-1 is part of the IRAK family consisting of IRAK-1, IRAK-2, IRAK-3, and IRAK-4, and is activated by inflammatory molecules released by signaling pathways during pathogenic attack. IRAK-1 is classified as a kinase enzyme, which regulates pathways in both innate and adaptive immune systems.
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 "discoveries concerning the activation of innate immunity." Beutler discovered the long-elusive receptor for lipopolysaccharide. He did so by identifying spontaneous mutations in the gene coding for mouse Toll-like receptor 4 (Tlr4) in two unrelated strains of LPS-refractory mice and proving they were responsible for that phenotype. Subsequently, and chiefly through the work of Shizuo Akira, other TLRs were shown to detect signature molecules of most infectious microbes, in each case triggering an innate immune response.
Toll interacting protein, also known as TOLLIP, is an inhibitory adaptor protein that in humans is encoded by the TOLLIP gene.
NF-kappa-B inhibitor zeta (IκBζ) is a protein that in humans is encoded by the NFKBIZ gene. This gene is a member of the ankyrin-repeat family and is induced by lipopolysaccharide (LPS). The C-terminal portion of the encoded product which contains the ankyrin repeats, shares high sequence similarity with the I kappa B family of proteins. The latter are known to play a role in inflammatory responses to LPS by their interaction with NF-κB proteins through ankyrin-repeat domains. Studies in mouse indicate that this gene product is one of the nuclear I kappa B proteins and an activator of IL-6 production. Two transcript variants encoding different isoforms have been found for this gene.
Interleukin-1 receptor-associated kinase 3 is an enzyme that in humans is encoded by the IRAK3 gene. Using in vivo liposome-mediated delivery of CRISPR/Cas9 plasmid expressing IRAK3 gRNA, IRAK3 was shown to be responsible for endotoxin-induced expression of A20 and VE-cadherin in endothelial cells. Thus, IRAK3 is crucial for maintenance and repair of endothelial barrier after endotoxin-induced lung injury.
Acyloxyacyl hydrolase, also known as AOAH, is a eukaryotic protein encoded by the AOAH gene. AOAH is produced by macrophages, dendritic cells, NK cells, ILC1 cells, neutrophils and renal proximal tubule cells.
Single Ig IL-1-related receptor (SIGIRR), also called Toll/Interleukin-1 receptor 8 (TIR8) or Interleukin-1 receptor 8 (IL-1R8), is transmembrane protein encoded by gene SIGIRR, which modulate inflammation, immune response, and tumorigenesis of colonic epithelial cells.
NOD-like receptor family pyrin domain containing 11 is a protein that in humans is encoded by the NLRP11 gene located on the long arm of human chromosome 19q13.42. NLRP11 belongs to the NALP subfamily, part of a large subfamily of CATERPILLER. It is also known as NALP11, PYPAF6, NOD17, PAN10, and CLR19.6
Roman Dziarski is a Polish-born American immunologist and microbiologist. He is best known for his research on innate immunity and bacterial peptidoglycan, for discovering the family of human peptidoglycan recognition proteins, which comprises PGLYRP1, PGLYRP2, PGLYRP3, and PGLYRP4, and for defining the functions of these proteins.
