Vitamin K-dependent carboxylation regulates Ca2+flux and adaptation to metabolic stress in (3 cells

Vitamin K is a micronutrient necessary for y-carboxylation of glutamic acids. This post-translational modifica-tion 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 (3 cells lacking y-carboxylation fail to adapt their insulin secretion in the context of age-related insulin resistance or diet-induced (3 cell stress. In human islets, y-carboxylase expression posi-tively correlates with improved insulin secretion in response to glucose. We identify endoplasmic reticulum Gla protein (ERGP) as a y-carboxylated ER-resident Ca2+-binding protein expressed in (3 cells. Mechanisti-cally, y-carboxylation of ERGP protects cells against Ca2+ overfilling by diminishing STIM1 and Orai1 interac-tion and restraining store-operated Ca2+ entry. These results reveal a critical role of vitamin K-dependent carboxylation in regulation of Ca2+ flux in (3 cells and in their capacity to adapt to metabolic stress.