PDF(Pubmed)
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.
摘要：
维生素K是谷氨酸的γ-羧化所必需的微量营养素。这种翻译后修饰发生在内质网(ER)中并影响分泌蛋白。最近的临床研究表明维生素K在糖尿病的病理生理学中，但是潜在的分子机制仍然未知。这里,我们表明，缺乏γ-羧化的小鼠β细胞在年龄相关的胰岛素抵抗或饮食诱导的β细胞应激的背景下无法适应其胰岛素分泌。在人类胰岛中，γ-羧化酶表达与响应于葡萄糖的胰岛素分泌改善正相关。我们将内质网Gla蛋白（ERGP）鉴定为在β细胞中表达的γ-羧化ER常驻Ca2结合蛋白。机械上,ERGP的γ-羧化通过减少STIM1和Orai1相互作用并限制存储操作的Ca2进入来保护细胞免受Ca2过量填充。这些结果揭示了维生素K依赖性羧化在调节β细胞中的Ca2通量及其适应代谢应激的能力中的关键作用。
