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

Vitamin K (VK) 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 VK in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown. Here, we show that β-cells lacking γ-carboxylation fail to adapt their insulin secretion in response to glucose in the context of age-related insulin resistance or diet-induced β-cell stress. Conversely, VK supplementation protects β-cells from ER stress-induced apoptosis. We identified junctate as a γ-carboxylated ER-resident protein expressed in β-cells, whose carboxylation is dysregulated in diabetic mouse models. Mechanistically, γ-carboxylation of junctate maintains basal cytosolic calcium levels and restrains store-operated calcium entry, by diminishing STIM1 and Orai1 puncta formation at the plasma membrane. These results reveal a critical role for γ- carboxylation in the regulation of calcium flux in β-cells and in their capacity to adapt to metabolic stress.