Cross-linking of the dermo-epidermal junction of skin regenerating from keratinocyte autografts. Anchoring fibrils are a target for tissue transglutaminase.

Raghunath, Michael; Höpfner, Bianca; Aeschlimann, Daniel; Lüthi, Urs; Meuli, Martin; Altermatt, Stefan; Gobet, Rita; Bruckner‐Tuderman, Leena; Steinmann, Beat

doi:10.1172/jci118901

Cited by 95 publications

(62 citation statements)

References 42 publications

(35 reference statements)

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“…Given the potential damage caused by hyperglycemia in both the glomerulus and mesangium (Mauer et al, 1984;Rasch, 1988;Ziyadeh and Goldfarb, 1991), the changes in ⑀-(␥-glutamyl)-lysine and tTg location would be consistent with the suggested role of tTg as a stress-related enzyme involved in tissue repair (Haroon et al, 1999;Mirza et al, 1997;Raghunath et al, 1996). However, previous studies have reported increased tTg levels accompanying externalization (Johnson et al, 1997 rather than just the redistribution of enzyme observed in the tubulointerstitium, an observation comparable to one we find in the glomerulus.…”

Section: Discussionmentioning

confidence: 74%

Increases in Renal ε-(γ-Glutamyl)-Lysine Crosslinks Result from Compartment-Specific Changes in Tissue Transglutaminase in Early Experimental Diabetic Nephropathy: Pathologic Implications

Skill

Griffin

Nahas

et al. 2001

Laboratory Investigation

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SUMMARY:Diabetic nephropathy (DN) is characterized by an early, progressive expansion and sclerosis of the glomerular mesangium leading to glomerulosclerosis. This is associated with parallel fibrosis of the renal interstitium. In experimental renal scarring, the protein cross-linking enzyme, tissue transglutaminase (tTg), is up-regulated and externalized causing an increase in its crosslink product, ⑀-(␥-glutamyl)-lysine, in the extracellular space. This potentially contributes to the extracellular matrix (ECM) accumulation central to tissue fibrosis by increasing deposition and inhibiting breakdown. We investigated if a similar mechanism may contribute to the ECM expansion characteristic of DN using the rat streptozotocin model over 120 days. Whole kidney ⑀-(␥-glutamyl)-lysine (HPLC analysis) was significantly increased from Day 90 (ϩ337%) and peaked at Day 120 (ϩ650%) (p Ͻ 0.05). Immunofluorescence showed this increase to be predominantly extracellular in the peritubular interstitial space, but also in individual glomeruli. Total kidney transglutaminase (Tg) was not elevated. However, using a Tg in situ activity assay, increased Tg was detected in both the extracellular interstitial space and glomeruli by Day 60, with a maximal 53% increase at Day 120 (p Ͻ 0.05). Using a specific anti-tTg antibody, immunohistochemistry showed a similar increase in extracellular enzyme in the interstitium and glomeruli. To biochemically characterize glomerular changes, glomeruli were isolated by selective sieving. In line with whole kidney measurement, there was an increase in glomerular ⑀-(␥-glutamyl) lysine (ϩ361%); however, in the glomeruli this was associated with increases in Tg activity (ϩ228%) and tTg antigen by Western blotting (ϩ215%). Importantly, the ratio of glomerular ⑀-(␥-glutamyl) lysine to hydroxyproline increased by 2.2-fold. In DN, changes in the kidney result in increased translocation of tTg to the extracellular environment where high Ca 2ϩ and low GTP levels allow its activation. In the tubulointerstitium this is independent of increased tTg production, but dependent in the glomerulus. This leads to excessive ECM cross-linking, contributing to the renal fibrosis characteristic of progressive DN. (Lab Invest 2001, 81:705-716).

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Section: Discussionmentioning

confidence: 74%

Increases in Renal ε-(γ-Glutamyl)-Lysine Crosslinks Result from Compartment-Specific Changes in Tissue Transglutaminase in Early Experimental Diabetic Nephropathy: Pathologic Implications

Skill

Griffin

Nahas

et al. 2001

Laboratory Investigation

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“…No other family member had a skin disease or a genetic disorder. The affected members of family 3 included the 7-year-old proband (3-1), his 5-year-old brother (3-2), the 36-year-old mother (3-3), the 33-year-old aunt (3)(4), and the 65-year-old grandfather (3)(4)(5). The father and grandfather of 3-5 as well as 13 other relatives in five generations reportedly suffered from similar mechanically induced skin blistering.…”

Section: Methodsmentioning

confidence: 99%

Some, but Not All, Glycine Substitution Mutations inCOL7A1 Result in Intracellular Accumulation of Collagen VII, Loss of Anchoring Fibrils, and Skin Blistering

Hammami-Hauasli¹,

Schumann²,

Raghunath³

et al. 1998

Journal of Biological Chemistry

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COL7A1 gene mutations cause dystrophic epidermolysis bullosa, a skin blistering disorder. The phenotypes result from defects of collagen VII, the major component of the anchoring fibrils at the dermo-epidermal junction; however, the molecular mechanisms underlying the phenotypes remain elusive. We investigated naturally occurring COL7A1 mutations and showed that some, but not all, glycine substitutions in collagen VII interfered with biosynthesis of the protein in a dominant-negative manner. Three point mutations in exon 73 caused glycine substitutions G2006D, G2034R, and G2015E in the triple helical domain of collagen VII and interfered with its folding and secretion. Confocal laser scanning studies and semiquantitative immunoblotting determined that dystrophic epidermolysis bullosa keratinocytes retained up to 2.5-fold more procollagen VII within the rough endoplasmic reticulum than controls. Limited proteolytic digestions of mutant procollagen VII produced aberrant fragments and revealed reduced stability of the triple helix. In contrast, the glycine substitution G1519D in another segment of the triple helix affected neither procollagen VII secretion nor anchoring fibril function and remained phenotypically silent. These data demonstrate that collagen VII presents a remarkable exception among collagens in that not all glycine substitutions within the triple helix exert dominant-negative interference and that the biological consequences of the substitutions probably depend on their position within the triple helix.Anchoring fibrils attach the epidermal basement membrane of the skin to the underlying dermal connective tissue (1, 2). They represent polymers of collagen VII, a large homotrimeric protein with a central triple helix and flanking amino-and carboxyl-terminal globular domains. Epidermal keratinocytes synthesize and secrete collagen VII as a triple helical precursor (procollagen VII) into the extracellular matrix. After secretion, procollagen VII undergoes proteolytic trimming to collagen VII (3) and assembles to polymers (1). This is a multistep process during which collagen VII monomers first form disulfidebonded antiparallel dimers and then laterally aggregate into anchoring fibrils, which interact with laminin 5 to secure the dermo-epidermal adhesion (1, 4). Further stabilization of anchoring fibrils and presumably of intermolecular aggregates is achieved through cross-linking by transglutaminase-2 (5). Anchoring fibrils are functionally deficient in hereditary dystrophic epidermolysis bullosa (DEB), 1 a heterogeneous group of bullous skin disorders (for reviews, see Refs. 6 and 7) with mechanically induced blistering and scarring of the skin. In the most severe forms of the disease, both collagen VII protein and anchoring fibrils are absent from the skin (8), whereas in milder forms, collagen VII is expressed, but the morphology of the anchoring fibrils may be altered (7, 9).Mutations in COL7A1 encoding collagen VII have been disclosed in both recessive and dominant DEB subtypes (10 -17). In reces...

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“…In addition to fibrin and fibronectin, tissue TGase has also been found to crosslink collagen III, V and VII [207], collagen XI, osteonectin [208] and osteopontin [8]. Localization of TGases has also been explored in ocular tissues [209][210][211].…”

Section: Tissue Transglutaminase Gluementioning

confidence: 99%

Tissue adhesives in ocular surgery

Park

Champakalakshmi

Panengad

et al. 2011

Expert Review of Ophthalmology

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Cross-linking of the dermo-epidermal junction of skin regenerating from keratinocyte autografts. Anchoring fibrils are a target for tissue transglutaminase.

Cited by 95 publications

References 42 publications

Increases in Renal ε-(γ-Glutamyl)-Lysine Crosslinks Result from Compartment-Specific Changes in Tissue Transglutaminase in Early Experimental Diabetic Nephropathy: Pathologic Implications

Increases in Renal ε-(γ-Glutamyl)-Lysine Crosslinks Result from Compartment-Specific Changes in Tissue Transglutaminase in Early Experimental Diabetic Nephropathy: Pathologic Implications

Some, but Not All, Glycine Substitution Mutations inCOL7A1 Result in Intracellular Accumulation of Collagen VII, Loss of Anchoring Fibrils, and Skin Blistering

Tissue adhesives in ocular surgery

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