Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Anatomy and Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland; Minerva Foundation Institute for Medical Research, Helsinki 00290, Finland.
Cell. 2018 Oct 4;175(2):514-529.e20. doi: 10.1016/j.cell.2018.08.033. Epub 2018 Sep 13.
The mechanisms underlying sterol transport in mammalian cells are poorly understood. In particular, how cholesterol internalized from HDL is made available to the cell for storage or modification is unknown. Here, we describe three ER-resident proteins (Aster-A, -B, -C) that bind cholesterol and facilitate its removal from the plasma membrane. The crystal structure of the central domain of Aster-A broadly resembles the sterol-binding fold of mammalian StARD proteins, but sequence differences in the Aster pocket result in a distinct mode of ligand binding. The Aster N-terminal GRAM domain binds phosphatidylserine and mediates Aster recruitment to plasma membrane-ER contact sites in response to cholesterol accumulation in the plasma membrane. Mice lacking Aster-B are deficient in adrenal cholesterol ester storage and steroidogenesis because of an inability to transport cholesterol from SR-BI to the ER. These findings identify a nonvesicular pathway for plasma membrane to ER sterol trafficking in mammals.
哺乳动物细胞中固醇运输的机制还了解甚少。特别是，从高密度脂蛋白（HDL）内化的胆固醇如何可供细胞储存或修饰尚不清楚。在这里，我们描述了三种内质网驻留蛋白（Aster-A、-B、-C），它们可以结合胆固醇并促进其从质膜中去除。Aster-A 的中心结构域的晶体结构与哺乳动物 StARD 蛋白的固醇结合折叠大致相似，但 Aster 口袋中的序列差异导致配体结合的独特模式。Aster N 端 GRAM 结构域结合磷脂酰丝氨酸，并介导 Aster 募集到质膜-内质网接触位点，以响应质膜中胆固醇的积累。缺乏 Aster-B 的小鼠由于不能将胆固醇从 SR-BI 转运到内质网，因此缺乏肾上腺胆固醇酯储存和类固醇生成。这些发现确定了哺乳动物质膜到内质网固醇运输的非小泡途径。
