The half-life of the bone-derived hormone osteocalcin is regulated throughO-glycosylation in mice, but not in humans

Abstract

Osteocalcin (OCN) is an osteoblast-derived hormone with pleiotropic physiological functions. Like many peptide hormones, OCN is subjected to post-translational modifications (PTMs) which control its activity. Here, we uncover O-glycosylation as a novel PTM present on mouse OCN and occurring on a single serine (S8) independently of its carboxylation and endoproteolysis, two other PTMs regulating this hormone. We also show that O-glycosylation increases OCN half-life in plasma ex vivo and in the circulation in vivo. Remarkably, in human OCN (hOCN), the residue corresponding to S8 is a tyrosine (Y12), which is not O-glycosylated. Yet, the Y12S mutation is sufficient to O-glycosylate hOCN and to increase its half-life in plasma compared to wildtype hOCN. These findings reveal an important species difference in OCN regulation, which may explain why serum concentrations of OCN are higher in mouse than in human.The authors have nothing to disclose

Genetic glycoengineering in mammalian cells

“…Similarly, a characteristic de novo expression of the GALNT6 isoenzyme in colon cancer was investigated by engineering GALNT s in a colon cancer cell line, and GALNT6 was selectively shown to affect differentiation and growth ( 152 ). The unique functions of several other GALNT isoenzymes were also explored in KO studies ( 153 , 154 , 155 , 156 , 157 , 158 , 159 ). Moreover, glycoengineering is being used with approaches for metabolic labeling and tagging of glycosylation ( 22 , 23 , 160 , 161 , 162 ), including the azido sugars for click chemistry introduced by the Bertozzi group ( 163 , 164 , 165 ).…”