Vitamin K-dependent γ-carboxylation regulates calcium flux and adaptation to metabolic stress in β-cells

SUMMARYVitamin K is a micronutrient necessary for the γ-carboxylation of glutamic acids. This post-translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Clinical studies have recently implicated 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 identified Endoplasmic Reticulum Gla Protein (ERGP) as a novel γ-carboxylated ER-resident calcium-binding protein expressed in β-cells. Mechanistically, γ-carboxylation of ERGP protects cells against calcium overfilling by diminishing STIM1 and Orai1 interaction and restraining store-operated calcium entry. These results reveal a critical role for vitamin K-dependent γ-carboxylation in the regulation of calcium flux in β-cells and in their capacity to adapt to metabolic stress.