Transglutaminases catalyze the posttranslational modification of proteins by transamidation of available glutamine residues. This action results primarily in the formation of epsilon-(gamma-glutamyl)lysine cross-links but includes the incorporation of polyamines into suitable protein substrates as well. The covalent isopeptide crosslink is stable and resistant to proteolysis, thereby increasing the resistance of tissue to chemical, enzymatic, and mechanical disruption. The plasma transglutaminase, factor XIIIa, is formed at sites of blood coagulation and impedes blood loss by stabilizing the fibrin clot. The squamous epithelium constituting the protective callus layer of skin is formed by the action of keratinocyte transglutaminase (TGK) and epidermal transglutaminase (TGE). The tissue transglutaminase (TGC) is a cytoplasmic enzyme present in many cells including those in the blood vessel wall. TGC function is unknown, although it could function to stabilize intra- and extra-cellular molecules in a wide v...

Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues.

This review covers major advances in clinical issues related to systemic lupus erythematosus (SLE) published between 1995 and 2000. The classification criteria for both SLE and antiphospholipid syndrome (APS) have been updated, and up to 19 different subsets of neuropsychiatric lupus have been defined. New epidemiological data show that the incidence of new cases and the survival of patients with SLE are both increasing. Several randomised controlled trials have defined the role of cyclophosphamide, methotrexate, antimalarials, and hormonal treatment in the management of SLE. New data are available for drugs such as ciclosporin and thalidomide. Finally, several new treatments for severe refractory cases, such as mycophenolate mofetil and stem-cell transplantation, are being increasingly used. New data also refer to management of thrombosis in APS and high-risk pregnancies in women with SLE or APS.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(07)60279-7.pdf

Systemic Lupus Erythematosus

A specialized tissue type, the keratinizing epithelium, protects terrestrial mammals from water loss and noxious physical, chemical and mechanical insults. This barrier between the body and the environment is constantly maintained by reproduction of inner living epidermal keratinocytes which undergo a process of terminal differentiation and then migrate to the surface as interlocking layers of dead stratum corneum cells. These cells provide the bulwark of mechanical and chemical protection, and together with their intercellular lipid surroundings, confer water-impermeability. Much of this barrier function is provided by the cornified cell envelope (CE), an extremely tough protein/lipid polymer structure formed just below the cytoplasmic membrane and subsequently resides on the exterior of the dead cornified cells. It consists of two parts: a protein envelope and a lipid envelope. The protein envelope is thought to contribute to the biomechanical properties of the CE as a result of cross-linking of specialized CE structural proteins by both disulfide bonds and N(epsilon)-(gamma-glutamyl)lysine isopeptide bonds formed by transglutaminases. Some of the structural proteins involved include involucrin, loricrin, small proline rich proteins, keratin intermediate filaments, elafin, cystatin A, and desmosomal proteins. The lipid envelope is located on the exterior of and covalently attached by ester bonds to the protein envelope and consists of a monomolecular layer of omega-hydroxyceramides. These not only serve of provide a Teflon-like coating to the cell, but also interdigitate with the intercellular lipid lamellae perhaps in a Velcro-like fashion. In fact the CE is a common feature of all stratified squamous epithelia, although its precise composition, structure and barrier function requirements vary widely between epithelia. Recent work has shown that a number of diseases which display defective epidermal barrier function, generically known as ichthyoses, are the result of genetic defects of the synthesis of either CE proteins, the transglutaminase 1 cross-linking enzyme, or defective metabolism of skin lipids.

/pdf/bricks-and-mortar-of-the-epidermal-barrier-2kvm8pin8b.pdf

Bricks and mortar of the epidermal barrier

The immunogenetics of Psoriasis: A comprehensive review.

Transglutaminases catalyze the posttranslational modification of proteins referred to as the R-glutaminyl peptide. a i rhc y glulur~~yl transferase reaction (EC 2.3.2.13). which leads to the formation of an isopeptide bond either within or between polypeptide chains. It appears that nature has not provided an enzyme for the cleavage of the transglutaminase cross-link in proteins. The action of these enzymes results therefore in the formation of "irreversibly" cross-linked, often insoluble supramolecular structures. In vertebrates, transglutaminases form a large protein family and have a wide distribution amongst tissues and body fluids. Proteins modified by transglutaminases are found throughout the organism, e. g. in fibrin clots formed in hemostasis and wound healing. in cell membranes of terminally differentiated erythrocytes. in extracellular matrices, and in the cornified envelope of the epidermis. Transglutaminases occur early in evolution and enzymes with a similar function to vertebrate transglutaminases have been found in invertebrates, in plants, in unicellular eucaryotes and in bacteria. While transglutaminases in higher animals always require Ca2+ for activity, thi? reqnirement is less stringent in plants and microorganism;. Recently, the p h a i y b11u~Lule u l a baclelial llar~aglulal~~iriast: was determined (1) and it was revealed that, these enzymes evolved as a separate lineage from the eucaryotic transglutaminases. For historical reasons several different names are used to describe a single transglutaminase gene product. The characterized gene products and the different designations are summarized in Table 1. The physiological function of the various transglutaminases is not well understood with the exception of the comparatively well characterized factor XIIIa. The widespread occurrence and high degree of conservation among transglutaminases could indicate that covalent protein cross-linking play? a more important role in nature than presently appreciated.

Transglutaminases: protein cross-linking enzymes in tissues and body fluids.

Substrates of human and bovine epidermal transglutaminase (glutaminyl-peptide gamma-glutamyltransferase, R-glutaminyl-peptide:amine-gamma-glutamyltransferase, EC 2.3.2.13) were isolated and purified by ion exchange chromatography and preparative zone electrophoresis. These substrates of Mr 36,000, which we propose to call keratolinin, incorporated dansylcadaverine and were precipitated by antibody. Keratolinin is ultimately polymerized on the inner leaflet of the keratinocyte membrane to form the cornified envelope. Each Mr 36,000 substrate was dissociated by chaotropic agents or detergents into noncovalent subunits; the Mr of these subunits was 6,000-6,200 on electrophoresis in 15% acrylamide/1% NaDodSO4/6 M urea gels. Isoelectric focusing of human or bovine keratolinin revealed two moieties separated by 0.3-0.4 pH unit (human, 5.4/5.0; bovine, 6.3/6.0). The two proteins were readily resolved by chromatofocusing and each isoelectric moiety of bovine keratolinin incorporated dansylcadaverine by epidermal transglutaminase and calcium and reacted with identity to antiserum to soluble Mr 36,000 keratolinin. Antiserum to human keratolinin failed to crossreact with its bovine counterpart. Antiserum to involucrin did not crossreact with either keratolinin or epidermis by immunodiffusion. Human and bovine epidermal keratolinins are biochemically similar but immunochemically distinct proteins from the epidermis. Involucrin appears only in significant quantities in cell culture.

Keratolinin: the soluble substrate of epidermal transglutaminase from human and bovine tissue.

Epidermal and hair follicle transglutaminases crosslink structural proteins in the skin by epsilon-(gammaglutamyl)-lysine bonds. This crosslinking produces protein polymers that are extremely insoluble and, until recently, difficult to characterize.

Epidermal and hair follicle transglutaminases and crosslinking in skin.

Biochemistry of Transglutaminases and Cross-Linking in the Skin

Diet-induced systemic lupus erythematosus (SLE) in primates.

Psoriasis vulgaris: a genetic approach.

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