期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：44
页码：15723-15728
DOI：10.1073/pnas.1417993111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceProteoglycans are cellular proteins modified with long chains of repeating sugar residues connected to serine residues within the protein core by a short tetrasaccharide linker. Proteoglycans perform critical cellular functions such as formation of the extracellular matrix, binding to a diverse array of molecules, and regulation of cell motility, adhesion, and cell-cell communication. We show here that family with sequence similarity 20, member B (Fam20B) is a xylose kinase that phosphorylates a xylose sugar residue within the proteoglycan tetrasaccharide linkage. Xylose phosphorylation dramatically stimulates the activity of galactosyltransferase II (GalT-II, B3GalT6), an enzyme that adds galactose to the growing linkage. Cells lacking Fam20B cannot extend the tetrasaccharide linkage and thus have immature and nonfunctional proteoglycan, a phenotype remarkably similar to Ehlers-Danlos syndrome caused by inactivating GalT-II mutations. Most eukaryotic cells elaborate several proteoglycans critical for transmitting biochemical signals into and between cells. However, the regulation of proteoglycan biosynthesis is not completely understood. We show that the atypical secretory kinase family with sequence similarity 20, member B (Fam20B) phosphorylates the initiating xylose residue in the proteoglycan tetrasaccharide linkage region, and that this event functions as a molecular switch to regulate subsequent glycosaminoglycan assembly. Proteoglycans from FAM20B knockout cells contain a truncated tetrasaccharide linkage region consisting of a disaccharide capped with sialic acid (Sia2-3Gal{beta}1-4Xyl{beta}1) that cannot be further elongated. We also show that the activity of galactosyl transferase II (GalT-II, B3GalT6), a key enzyme in the biosynthesis of the tetrasaccharide linkage region, is dramatically increased by Fam20B-dependent xylose phosphorylation. Inactivating mutations in the GALT-II gene (B3GALT6) associated with Ehlers-Danlos syndrome cause proteoglycan maturation defects similar to FAM20B deletion. Collectively, our findings suggest that GalT-II function is impaired by loss of Fam20B-dependent xylose phosphorylation and reveal a previously unappreciated mechanism for regulation of proteoglycan biosynthesis.
