title: Xylose phosphorylation functions as a molecular switch to regulate proteoglycan biosynthesis.
abstract: 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 (Siaα2-3Galβ1-4Xylβ1) 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.
authors.affiliation: Departments of Pharmacology and.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Wen
authors.affiliation: Departments of Pharmacology and.
authors.forename: Junyu
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Departments of Pharmacology and.
authors.forename: Meghdad
authors.initials: M
authors.lastname: Rahdar
authors.affiliation: Cellular and Molecular Medicine, and.
authors.forename: Biswa P
authors.initials: BP
authors.lastname: Choudhury
authors.affiliation: Departments of Pharmacology and.
authors.forename: Jixin
authors.initials: J
authors.lastname: Cui
authors.affiliation: Departments of Pharmacology and.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Taylor
authors.affiliation: Cellular and Molecular Medicine, and Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.affiliation: Departments of Pharmacology and jedixon@ucsd.edu.
authors.forename: Jack E
authors.initials: JE
authors.lastname: Dixon
mesh_terms: D004535:Ehlers-Danlos Syndrome / Q000235:genetics / Q000378:metabolism; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation / Q000235:genetics; D011509:Proteoglycans / Q000096:biosynthesis* / Q000235:genetics; D012794:Sialic Acids / Q000235:genetics / Q000378:metabolism*; D014994:Xylose / Q000235:genetics / Q000378:metabolism*
chemical_list: D011509:Proteoglycans; D012794:Sialic Acids; D014994:Xylose; C425302:B3GALT6 protein, human; D005700:Galactosyltransferases
keywords: Fam20B; GalT-II; proteoglycan; secretory kinase; xylose phosphorylation