Vitamin K-dependent carboxylation regulates Ca(2+) flux and adaptation to metabolic stress in β cells

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 Ca(2+)-binding protein expressed in β cells. Mechanistically, γ-carboxylation of ERGP protects cells against Ca(2+) overfilling by diminishing STIM1 and Orai1 interaction and restraining store-operated Ca(2+) entry. These results reveal a critical role of vitamin K-dependent carboxylation in regulation of Ca(2+) flux in β cells and in their capacity to adapt to metabolic stress.