StarD5: an ER stress protein regulates plasma membrane and intracellular cholesterol homeostasis
StarD5: an ER stress protein regulates plasma membrane and intracellular cholesterol homeostasis
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DOI：
10.1194/jlr.m091967
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发表时间：
2019-06-01
影响因子：
6.5
通讯作者：
Gil, Gregorio
中科院分区：
文献类型：
--
作者：
Rodriguez-Agudo, Daniel;Malacrida, Leonel;Gil, Gregorio
人们对质膜 (PM) 胆固醇的控制机制知之甚少。消除编码 ER 应激类固醇生成急性调节相关脂质转移结构域 (StarD)5 的基因会导致 PM 胆固醇含量降低、胆固醇流出减少以及巨噬细胞（表达 StarD5 的主要细胞类型）细胞内中性脂质积累增加。 ER应激增加了小鼠肝细胞中StarD5的表达，从而导致WT中可接近的PM胆固醇增加，但StarD5(-/-)肝细胞中则没有增加。 StarD5(-/-) 小鼠储存较高水平的胆固醇和甘油三酯，这导致胆固醇调节基因的表达改变。在体外，重组 GST-StarD5 蛋白在合成脂质体之间转移胆固醇。 StarD5 过度表达导致 PM 胆固醇显着增加。 6-十二酰基-2-二甲氨基萘荧光寿命成像显微镜数据的相量分析揭示了 StarD5(-/-) 巨噬细胞中 PM 流动性的增加。总而言之，这些研究表明 StarD5 是一种应激反应蛋白，可调节 PM 胆固醇和细胞内胆固醇稳态。
How plasma membrane (PM) cholesterol is controlled is poorly understood. Ablation of the gene encoding the ER stress steroidogenic acute regulatory-related lipid transfer domain (StarD)5 leads to a decrease in PM cholesterol content, a decrease in cholesterol efflux, and an increase in intracellular neutral lipid accumulation in macrophages, the major cell type that expresses StarD5. ER stress increases StarD5 expression in mouse hepatocytes, which results in an increase in accessible PM cholesterol in WT but not in StarD5(-/-) hepatocytes. StarD5(-/-) mice store higher levels of cholesterol and triglycerides, which leads to altered expression of cholesterol-regulated genes. In vitro, a recombinant GST-StarD5 protein transfers cholesterol between synthetic liposomes. StarD5 overexpression leads to a marked increase in PM cholesterol. Phasor analysis of 6-dodecanoyl-2-dimethylaminonaphthalene fluorescence lifetime imaging microscopy data revealed an increase in PM fluidity in StarD5(-/-) macrophages. Taken together, these studies show that StarD5 is a stress-responsive protein that regulates PM cholesterol and intracellular cholesterol homeostasis.