Human Xylosyltransferase II Is Involved in the Biosynthesis of the Uniform Tetrasaccharide Linkage Region in Chondroitin Sulfate and Heparan Sulfate Proteoglycans

Pönighaus, Claudia; Ambrosius, Michael; Casanova, Javier Carrera; Prante, Christian; Kühn, Joachim; Esko, Jeffrey D.; Kleesiek, Knut; Götting, Christian

doi:10.1074/jbc.m611665200

Cited by 93 publications

(95 citation statements)

References 31 publications

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“…Both enzymes are capable of initiating the biosynthesis of chondroitin sulfate, dermatan sulfate, and heparan sulfate glycosaminoglycan chains (17,30,31). Until now we and others have not found any differences of both xylosyltransferases in regards to acceptor specificity or a preference for the biosynthesis of either chondroitin sulfate or heparan sulfate proteoglycans.…”

Section: Discussionmentioning

confidence: 95%

“…The GAGs chondroitin sulfate, dermatan sulfate, heparan sulfate, and heparin are bound to the proteoglycan core protein by a xylose-galactose-galactose binding region. Xylosyltransferase I (XT-I) and xylosyltransferase II (XT-II) are the initiating and apparently rate-limiting enzymes involved in GAG biosynthesis catalyzing the transfer of UDP-xylose to specific serine residues of the core proteins (15)(16)(17). We have shown previously that the XT-I enzyme is secreted from the endoplasmic reticulum into the extracellular space together with chondroitin sulfate (CS) proteoglycans (18).…”

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confidence: 99%

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Transforming Growth Factor β1-regulated Xylosyltransferase I Activity in Human Cardiac Fibroblasts and Its Impact for Myocardial Remodeling

Prante

Milting

Kassner

et al. 2007

Journal of Biological Chemistry

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In cardiac fibrosis remodeling of the failing myocardium is associated with a complex reorganization of the extracellular matrix (ECM). Xylosyltransferase I and Xylosyltransferase II (XT-I and XT-II) are the key enzymes in proteoglycan biosynthesis, which are an important fraction of the ECM. XT-I was shown to be a measure for the proteoglycan biosynthesis rate and a biochemical fibrosis marker. Here, we investigated the XT-I and XT-II expression in cardiac fibroblasts and in patients with dilated cardiomyopathy and compared our findings with nonfailing donor hearts. We analyzed XT-I and XT-II expression and the glycosaminoglycan (GAG) content in human cardiac fibroblasts incubated with transforming growth factor (TGF)-␤ 1 or exposed to cyclic mechanical stretch. In vitro and in vivo no significant changes in the XT-II expression were detected. For XT-I we found an increased expression in parallel with an elevated chondroitin sulfate-GAG content after incubation with TGF-␤ 1 and after mechanical stretch. XT-I expression and subsequently increased levels of GAGs could be reduced with neutralizing anti-TGF-␤ 1 antibodies or by specific inhibition of the activin receptor-like kinase 5 or the p38 mitogen-activated protein kinase pathway. Usage of XT-I small interfering RNA could specifically block the increased XT-I expression under mechanical stress and resulted in a significantly reduced chondroitin sulfate-GAG content. In the left and right ventricular samples of dilated cardiomyopathy patients, our data show increased amounts of XT-I mRNA compared with nonfailing controls. Patients had raised levels of XT-I enzyme activity and an elevated proteoglycan content. Myocardial remodeling is characterized by increased XT-I expression and enhanced proteoglycan deposition. TGF-␤ 1 and mechanical stress induce XT-I expression in cardiac fibroblasts and have impact for ECM remodeling in the dilated heart. Specific blocking of XT-I expression confirmed that XT-I catalyzes a rate-limiting step during fibrotic GAG biosynthesis.

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

Transforming Growth Factor β1-regulated Xylosyltransferase I Activity in Human Cardiac Fibroblasts and Its Impact for Myocardial Remodeling

Prante

Milting

Kassner

et al. 2007

Journal of Biological Chemistry

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“…The enzyme transferred xylose from UDP-d-xylose to serine residues in bikunin, silk and other core proteins, forming a blinkage which was selectively labile to b-xylosidase treatment and alkaline b-elimination [18]. Full-length forms of human XT-I have also been successfully expressed in CHO [25], HEK293 and SaOS-2 cells [19]. During cloning the cDNA of human XT-I, another cDNA from human and rat sources was cloned which coded for a different protein with high homology to XT-I (Fig.…”

Section: Purification and Cloning Of The Xylosyltransferasesmentioning

confidence: 97%

Human xylosyltransferases in health and disease

Götting

Kühn

Kleesiek

2007

Cell. Mol. Life Sci.

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The xylosyltransferases I and II (XT-I, XT-II, EC 2.4.2.26) catalyze the transfer of xylose from UDP-xylose to selected serine residues in the proteoglycan core protein, which is the initial and ratelimiting step in glycosaminoglycan biosynthesis. Both xylosyltransferases are Golgi-resident enzymes and transfer xylose to similar core proteins acceptors. XT-I and XT-II are differentially expressed in cell types and tissues, although the reason for the existence of two xylosyltransferase isoforms in all higher organisms remains elusive. Serum xylosyltransferase activity was found to be a biochemical marker for the assessment of disease activity in systemic sclerosis and for the diagnosis of fibrotic remodeling processes. Furthermore, sequence variations in the XT-I and XT-II coding genes were identified as risk factors for diabetic nephropathy, osteoarthritis or pseudoxanthoma elasticum. These findings point to the important role of the xylosyltransferases as disease modifiers in pathologies which are characterized by an altered proteoglycan metabolism. The present review discusses recent advances in mammalian xylosyltransferases and the impact of xylosyltransferases in proteoglycan-associated diseases.

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“…We have investigated the role that PGs play in the development of human polycystic disease by inactivating xylosyltransferase 2 [(XylT2) Enzyme Commission no. 2.4.2.26], an enzyme shown to be involved in HS and CS biosynthesis (25)(26)(27). We have shown in an experimental model system that reduced PGs are cystogenic.…”

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confidence: 99%

Polycystic disease caused by deficiency in xylosyltransferase 2, an initiating enzyme of glycosaminoglycan biosynthesis

Condac

Silasi‐Mansat

Kosanke

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The basic biochemical mechanisms underlying many heritable human polycystic diseases are unknown despite evidence that most cases are caused by mutations in members of several protein families, the most prominent being the polycystin gene family, whose products are found on the primary cilia, or due to mutations in posttranslational processing and transport. Inherited polycystic kidney disease, the most prevalent polycystic disease, currently affects Ϸ500,000 people in the United States. Decreases in proteoglycans (PGs) have been found in tissues and cultured cells from patients who suffer from autosomal dominant polycystic kidney disease, and this PG decrease has been hypothesized to be responsible for cystogenesis. This is possible because alterations in PG concentrations would be predicted to disrupt many homeostatic mechanisms of growth, development, and metabolism. To test this hypothesis, we have generated mice lacking xylosyltransferase 2 (XylT2), an enzyme involved in PG biosynthesis. Here we show that inactivation of XylT2 results in a substantial reduction in PGs and a phenotype characteristic of many aspects of polycystic liver and kidney disease, including biliary epithelial cysts, renal tubule dilation, organ fibrosis, and basement membrane abnormalities. Our findings demonstrate that alterations in PG concentrations can occur due to loss of XylT2, and that reduced PGs can induce cyst development.animal model ͉ extracellular matrix ͉ genetics ͉ proteoglycans ͉ cyst

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Human Xylosyltransferase II Is Involved in the Biosynthesis of the Uniform Tetrasaccharide Linkage Region in Chondroitin Sulfate and Heparan Sulfate Proteoglycans

Cited by 93 publications

References 31 publications

Transforming Growth Factor β1-regulated Xylosyltransferase I Activity in Human Cardiac Fibroblasts and Its Impact for Myocardial Remodeling

Transforming Growth Factor β1-regulated Xylosyltransferase I Activity in Human Cardiac Fibroblasts and Its Impact for Myocardial Remodeling

Human xylosyltransferases in health and disease

Polycystic disease caused by deficiency in xylosyltransferase 2, an initiating enzyme of glycosaminoglycan biosynthesis

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