{Reference Type}: Journal Article
{Title}: Vitamin K-dependent carboxylation regulates Ca2+ flux and adaptation to metabolic stress in β cells.
{Author}: Lacombe J;Guo K;Bonneau J;Faubert D;Gioanni F;Vivoli A;Muir SM;Hezzaz S;Poitout V;Ferron M;
{Journal}: Cell Rep
{Volume}: 42
{Issue}: 5
{Year}: 2023 05 30
暂无{DOI}: 10.1016/j.celrep.2023.112500
{Abstract}: 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.