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.
Highlights
Osteocalcin (OCN) is a peptide hormone secreted by osteoblasts, the bone forming cells (Lee et al, 2007)
Since OCN Gla residues and pro-OCN cleavage site are conserved between mouse and human, we searched for additional post-translational modifications (PTMs) present in mouse OCN and characterized their impact on OCN half-life
According to the various monoisotopic masses observed, we predict that this difference could be mainly explained by the presence of a single O-linked glycan adduct composed of one N-acetylgalactosamine (GalNAc), one galactose (Gal) and one or two N-acetylneuraminic acid (NANA)
Summary
Osteocalcin (OCN) is a peptide hormone secreted by osteoblasts, the bone forming cells (Lee et al, 2007). Al Rifai et al showed that when human osteocalcin was modified so the sugar group could attach, the hormone was able to stick around for much longer and reach higher levels when added to blood in the laboratory These findings show how osteocalcin differs between human and mice. The circulating concentrations of OCN, even though decreasing with age in both species, are five to ten times higher in mice than in humans throughout life span [(Mera et al, 2016a) see Table 1] Based on these observations, we hypothesized that the post-translational regulation of OCN may be different between these two species, resulting in increased mouse OCN half-life in circulation. A single point mutation in human OCN is sufficient to elicit its O-glycosylation and to increase its half-life in plasma
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