%0 Journal Article
%T Vitamin K-dependent carboxylation regulates Ca2+ flux and adaptation to metabolic stress in β cells.
%A Lacombe J
%A Guo K
%A Bonneau J
%A Faubert D
%A Gioanni F
%A Vivoli A
%A Muir SM
%A Hezzaz S
%A Poitout V
%A Ferron M
%J Cell Rep
%V 42
%N 5
%D 2023 05 30
%M 37171959
暂无%R 10.1016/j.celrep.2023.112500
%X 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.