Site-specific protein O-glycosylation modulates proprotein processing — Deciphering specific functions of the large polypeptide GalNAc-transferase gene family

• Published in: Biochimica et biophysica acta 2012-12, Vol.1820 (12), p.2079-2094
• Main Authors: Schjoldager, Katrine T.-B.G., Clausen, Henrik
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; biosynthesis; Congenital disorder of glycosylation (CDG); Fibroblast Growth Factor-23; GalNAc-transferase (UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase); gene expression regulation; gene targeting; genes; Glycoproteins - metabolism; Glycosylation; human cell lines; human diseases; Humans; lipid metabolism; Molecular Sequence Data; Multigene Family; N-Acetylgalactosaminyltransferases - genetics; N-Acetylgalactosaminyltransferases - metabolism; O-glycosylation; phenotype; Polypeptide N-acetylgalactosaminyltransferase; polypeptides; post-translational modification; Pro-protein convertase (PC) processing; Proprotein Convertases - metabolism; Protein Processing, Post-Translational; proteinases; proteins; proteolysis; zinc finger motif; Zinc finger nuclease gene targeting
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.09.014

Posttranslational modifications (PTMs) greatly expand the function and regulation of proteins, and glycosylation is the most abundant and diverse PTM. Of the many different types of protein glycosylation, one is quite unique; GalNAc-type (or mucin-type) O-glycosylation, where biosynthesis is initiated in the Golgi by up to twenty distinct UDP-N-acetyl-α-d-galactosamine:polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts). These GalNAc-Ts are differentially expressed in cells and have different (although partly overlapping) substrate specificities, which provide for both unique functions and considerable redundancy. Recently we have begun to uncover human diseases associated with deficiencies in GalNAc-T genes (GALNTs). Thus deficiencies in individual GALNTs produce cell and protein specific effects and subtle distinct phenotypes such as hyperphosphatemia with hyperostosis (GALNT3) and dysregulated lipid metabolism (GALNT2). These phenotypes appear to be caused by deficient site-specific O-glycosylation that co-regulates proprotein convertase (PC) processing of FGF23 and ANGPTL3, respectively. Here we summarize recent progress in uncovering the interplay between human O-glycosylation and protease regulated processing and describes other important functions of site-specific O-glycosylation in health and disease. Site-specific O-glycosylation modifies pro-protein processing and other proteolytic events such as ADAM processing and thus emerges as an important co-regulator of limited proteolytic processing events. Our appreciation of this function may have been hampered by our sparse knowledge of the O-glycoproteome and in particular sites of O-glycosylation. New strategies for identification of O-glycoproteins have emerged and recently the concept of SimpleCells, i.e. human cell lines made deficient in O-glycan extension by zinc finger nuclease gene targeting, was introduced for broad O-glycoproteome analysis. ► Up to 20 GalNAc-T isoforms catalyze the initiation of GalNAc-type O-glycosylation. ► O-glycosylation modulates proteolytic processing by PC convertases and ADAMs. ► Deficiencies in GalNAc-Ts cause protein specific effects and distinct phenotypes. ► New glyco-proteomic strategy for discovery of new targets of O-glycosylation/processing