The half-life of the bone-derived hormone osteocalcin is regulated through O-glycosylation in mice, but not in humans
Omar Al Rifai,
Catherine Julien,
Julie Lacombe,
Denis Faubert,
Erandi Lira-Navarrete,
Yoshiki Narimatsu,
Henrik Clausen,
Mathieu Ferron
Affiliations
Omar Al Rifai
Molecular Physiology Research unit, Institut de Recherches Cliniques de Montréal, Montréal, Canada; Programme de biologie moléculaire, Université de Montréal, Montréal, Canada
Catherine Julien
Molecular Physiology Research unit, Institut de Recherches Cliniques de Montréal, Montréal, Canada
Julie Lacombe
Molecular Physiology Research unit, Institut de Recherches Cliniques de Montréal, Montréal, Canada
Denis Faubert
Proteomics Discovery Platform, Institut de Recherches Cliniques de Montréal, Montréal, Canada
Erandi Lira-Navarrete
University of Copenhagen, Faculty of Health Sciences, Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Copenhagen, Denmark
Yoshiki Narimatsu
University of Copenhagen, Faculty of Health Sciences, Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Copenhagen, Denmark
Henrik Clausen
University of Copenhagen, Faculty of Health Sciences, Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Copenhagen, Denmark
Molecular Physiology Research unit, Institut de Recherches Cliniques de Montréal, Montréal, Canada; Programme de biologie moléculaire, Université de Montréal, Montréal, Canada; Département de Médecine, Université de Montréal, Montréal, Canada; Division of Experimental Medicine, McGill University, Montréal, Canada
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.
