title: Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation.
abstract: Mutations in the gene encoding the glycosyltransferase polypeptide GalNAc-T3, which is involved in initiation of O-glycosylation, were recently identified as a cause of the rare autosomal recessive metabolic disorder familial tumoral calcinosis (OMIM 211900). Familial tumoral calcinosis is associated with hyperphosphatemia and massive ectopic calcifications. Here, we demonstrate that the secretion of the phosphaturic factor fibroblast growth factor 23 (FGF23) requires O-glycosylation, and that GalNAc-T3 selectively directs O-glycosylation in a subtilisin-like proprotein convertase recognition sequence motif, which blocks processing of FGF23. The study suggests a novel posttranslational regulatory model of FGF23 involving competing O-glycosylation and protease processing to produce intact FGF23.
authors.affiliation: Department of Medical Biochemistry and Genetics, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kato
authors.forename: Charlotte
authors.initials: C
authors.lastname: Jeanneau
authors.forename: Mads Agervig
authors.initials: MA
authors.lastname: Tarp
authors.forename: Anna
authors.initials: A
authors.lastname: Benet-Pagès
authors.forename: Bettina
authors.initials: B
authors.lastname: Lorenz-Depiereux
authors.forename: Eric Paul
authors.initials: EP
authors.lastname: Bennett
authors.forename: Ulla
authors.initials: U
authors.lastname: Mandel
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Henrik
authors.initials: H
authors.lastname: Clausen
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002114:Calcinosis / Q000235:genetics* / Q000378:metabolism; D006224:Cricetinae; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D008659:Metabolic Diseases / Q000235:genetics; D008969:Molecular Sequence Data; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D013379:Substrate Specificity; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors; D017350:N-Acetylgalactosaminyltransferases; D009363:Neoplasm Proteins; D043484:Proprotein Convertases; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C000717427:FGF23 protein, human