Mutagenesis of the putative sterol-sensing domain of yeast Niemann Pick C-related protein reveals a primordial role in subcellular sphingolipid distribution.
Mutagenesis of the putative sterol-sensing domain of yeast Niemann Pick C-related protein reveals a primordial role in subcellular sphingolipid distribution.
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DOI：
10.1083/jcb.200310046
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发表时间：
2004-02-16
期刊：
影响因子：
--
通讯作者：
Sturley SL
中科院分区：
文献类型：
--
作者：
Malathi K;Higaki K;Tinkelenberg AH;Balderes DA;Almanzar-Paramio D;Wilcox LJ;Erdeniz N;Redican F;Padamsee M;Liu Y;Khan S;Alcantara F;Carstea ED;Morris JA;Sturley SL
细胞器间的脂质运动是真核膜动态平衡的重要组成部分。Niemann Pick C型(NP-C)病是一种致命的神经退行性疾病，其典型特征是溶酶体中胆固醇和鞘磷脂的堆积。人NP-C基因1(NPC1)的同源基因酵母NP-C相关基因1(NCR1)在中国仓鼠卵巢NPC1突变细胞中的表达抑制了脂质的积累。缺失的NCR1编码一种主要存在于正常酵母液泡中的跨膜糖蛋白，没有给出任何表型。然而，Ncr1p假定的类固醇敏感结构域上的一个显性突变赋予温度和多烯抗生素敏感性，而不改变类固醇代谢。相反，突变的细胞对鞘磷脂生物合成的抑制剂具有抵抗力，而对鞘氨醇和C2-神经酰胺超敏感。此外，突变体细胞的质膜鞘磷脂积累并重新分布到液泡和其他亚细胞膜。我们认为，这些蛋白质的原始功能是回收鞘磷脂，在高等真核生物中，这一过程的缺陷继而导致胆固醇积累。
Lipid movement between organelles is a critical component of eukaryotic membrane homeostasis. Niemann Pick type C (NP-C) disease is a fatal neurodegenerative disorder typified by lysosomal accumulation of cholesterol and sphingolipids. Expression of yeast NP-C–related gene 1 (NCR1), the orthologue of the human NP-C gene 1 (NPC1) defective in the disease, in Chinese hamster ovary NPC1 mutant cells suppressed lipid accumulation. Deletion of NCR1, encoding a transmembrane glycoprotein predominantly residing in the vacuole of normal yeast, gave no phenotype. However, a dominant mutation in the putative sterol-sensing domain of Ncr1p conferred temperature and polyene antibiotic sensitivity without changes in sterol metabolism. Instead, the mutant cells were resistant to inhibitors of sphingolipid biosynthesis and super sensitive to sphingosine and C2-ceramide. Moreover, plasma membrane sphingolipids accumulated and redistributed to the vacuole and other subcellular membranes of the mutant cells. We propose that the primordial function of these proteins is to recycle sphingolipids and that defects in this process in higher eukaryotes secondarily result in cholesterol accumulation.
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