STARD4 abundance regulates sterol transport and sensing.
STARD4 abundance regulates sterol transport and sensing.
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DOI：
10.1091/mbc.e11-04-0372
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发表时间：
2011-11
影响因子：
3.3
通讯作者：
Maxfield FR
中科院分区：
文献类型：
--
作者：
Mesmin B;Pipalia NH;Lund FW;Ramlall TF;Sokolov A;Eliezer D;Maxfield FR
小固醇转运蛋白STARD 4的表达受胆固醇水平调节。我们发现，STARD 4的丰度调节SREBP-2系统对胆固醇变化的敏感性，为胆固醇稳态机制提供了额外的调节层。胆固醇的非囊泡转运在细胞内胆固醇的分布和调节中起着至关重要的作用，但一直难以确定关键的细胞内胆固醇转运蛋白。类固醇生成急性调节相关脂质转移（START）蛋白家族参与了甾醇非囊泡运输的几种途径。其中，STARD 4已显示增加细胞内胆固醇酯的形成，并且在转录水平上受细胞中固醇水平的控制。我们发现STARD 4在体外膜之间转运固醇非常有效。在STARD 4沉默的细胞中胆固醇水平增加，而在STARD 4过表达时，固醇转运到内吞再循环室（ERC）和内质网（ER）增强。STARD 4沉默减弱胆固醇介导的SREBP-2激活调节，而其过表达增强SCAP/SREBP-2的固醇传感。为了分析STARD 4的作用模式，我们比较了STARD 4介导的甾醇转运与简单的甾醇载体甲基-β-环糊精（MCD），当STARD 4和MCD过表达或注射到细胞中时。有趣的是，STARD 4和胞质MCD通过增加固醇向ERC和ER的转移速率起相似的作用。我们的研究结果表明，由STARD 4介导的胆固醇转运是胆固醇稳态调节机制的重要组成部分。
The expression of a small sterol transport protein, STARD4, is regulated by cholesterol levels. We show that the abundance of STARD4 regulates the sensitivity of the SREBP-2 system to changes in cholesterol, providing an additional layer of regulation in the cholesterol homeostatic mechanism. Nonvesicular transport of cholesterol plays an essential role in the distribution and regulation of cholesterol within cells, but it has been difficult to identify the key intracellular cholesterol transporters. The steroidogenic acute regulatory-related lipid-transfer (START) family of proteins is involved in several pathways of nonvesicular trafficking of sterols. Among them, STARD4 has been shown to increase intracellular cholesteryl ester formation and is controlled at the transcriptional level by sterol levels in cells. We found that STARD4 is very efficient in transporting sterol between membranes in vitro. Cholesterol levels are increased in STARD4-silenced cells, while sterol transport to the endocytic recycling compartment (ERC) and to the endoplasmic reticulum (ER) are enhanced upon STARD4 overexpression. STARD4 silencing attenuates cholesterol-mediated regulation of SREBP-2 activation, while its overexpression amplifies sterol sensing by SCAP/SREBP-2. To analyze STARD4's mode of action, we compared sterol transport mediated by STARD4 with that of a simple sterol carrier, methyl-β-cyclodextrin (MCD), when STARD4 and MCD were overexpressed or injected into cells. Interestingly, STARD4 and cytosolic MCD act similarly by increasing the rate of transfer of sterol to the ERC and to the ER. Our results suggest that cholesterol transport mediated by STARD4 is an important component of the cholesterol homeostasis regulatory machinery.