Vitamin K-dependent carboxylation regulates Ca2+ flux and adaptation to metabolic stress in β cells
Julie Lacombe,
Kevin Guo,
Jessica Bonneau,
Denis Faubert,
Florian Gioanni,
Alexis Vivoli,
Sarah M. Muir,
Soraya Hezzaz,
Vincent Poitout,
Mathieu Ferron
Affiliations
Julie Lacombe
Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada; Corresponding author
Kevin Guo
Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada; Division of Experimental Medicine, McGill University, Montréal, QC H4A 3J1, Canada
Jessica Bonneau
Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada; Programme de Biologie Moléculaire, Université de Montréal, Montréal, QC H3T 1J4, Canada
Denis Faubert
Mass Spectrometry and Proteomics Platform, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada
Florian Gioanni
Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada
Alexis Vivoli
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada
Sarah M. Muir
Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada
Soraya Hezzaz
Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada
Vincent Poitout
Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC H2X 0A9, Canada; Département de Médecine, Université de Montréal, Montréal, QC H3T 1J4, Canada
Mathieu Ferron
Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada; Division of Experimental Medicine, McGill University, Montréal, QC H4A 3J1, Canada; Programme de Biologie Moléculaire, Université de Montréal, Montréal, QC H3T 1J4, Canada; Département de Médecine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Corresponding author
Summary: Vitamin K is a micronutrient necessary for γ-carboxylation of glutamic acids. This post-translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Recent clinical studies implicate vitamin K in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown. Here, we show that mouse β cells lacking γ-carboxylation fail to adapt their insulin secretion in the context of age-related insulin resistance or diet-induced β cell stress. In human islets, γ-carboxylase expression positively correlates with improved insulin secretion in response to glucose. We identify endoplasmic reticulum Gla protein (ERGP) as a γ-carboxylated ER-resident Ca2+-binding protein expressed in β cells. Mechanistically, γ-carboxylation of ERGP protects cells against Ca2+ overfilling by diminishing STIM1 and Orai1 interaction and restraining store-operated Ca2+ entry. These results reveal a critical role of vitamin K-dependent carboxylation in regulation of Ca2+ flux in β cells and in their capacity to adapt to metabolic stress.
