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高通量遗传学揭示的磷脂结合蛋白的惊人作用。

Surprising roles for phospholipid binding proteins revealed by high throughput genetics.

机构信息

Department of Pediatrics and Department of Biochemistry and Molecular Biology, Atlantic Research Centre, Dalhousie University, Halifax, NS, Canada.

出版信息

Biochem Cell Biol. 2010 Aug;88(4):565-74. doi: 10.1139/O09-171.

Abstract

Saccharomyces cerevisiae remains an ideal organism for studying the cell biological roles of lipids in vivo, as yeast has phospholipid metabolic pathways similar to mammalian cells, is easy and economical to manipulate, and is genetically tractable. The availability of isogenic strains containing specific genetic inactivation of each non-essential gene allowed for the development of a high-throughput method, called synthetic genetic analysis (SGA), to identify and describe precise pathways or functions associated with specific genes. This review describes the use of SGA to aid in elucidating the function of two lipid-binding proteins that regulate vesicular transport, Sec14 and Kes1. Sec14 was first identified as a phosphatidylcholine (PC) - phosphatidylinositol (PI) transfer protein required for viability, with reduced Sec14 function resulting in diminished vesicular transport out of the trans-Golgi. Although Sec14 is required for cell viability, inactivating the KES1 gene that encodes for a member of the oxysterol binding protein family in cells lacking Sec14 function results in restoration of vesicular transport and cell growth. SGA analysis identified a role for Kes1 and Sec14 in regulating the level and function of Golgi PI-4-phosphate (PI-4-P). SGA also determined that Sec14 not only regulates vesicular transport out of the trans-Golgi, but also transport from endosomes to the trans-Golgi. Comparing SGA screens in databases, coupled with genetic and cell biological analyses, further determined that the PI-4-P pool affected by Kes1 is generated by the PI 4-kinase Pik1. An important biological role for Sec14 and Kes1 revealed by SGA is coordinate regulation of the Pik1-generated Golgi PI-4-P pool that in turn is essential for vesicular transport into and out of the trans-Golgi.

摘要

酿酒酵母仍然是研究体内脂质的细胞生物学作用的理想生物,因为酵母具有与哺乳动物细胞相似的磷脂代谢途径,易于操作且经济,并且具有遗传可操作性。具有特定非必需基因遗传失活的同基因株系的可用性允许开发一种高通量方法,称为合成遗传分析(SGA),以鉴定和描述与特定基因相关的特定途径或功能。本文综述了 SGA 在阐明两种调节囊泡运输的脂质结合蛋白(Sec14 和 Kes1)的功能中的应用。Sec14 最初被鉴定为一种必需的 PC-磷脂酰肌醇(PI)转移蛋白,其功能降低导致囊泡从反式高尔基体中运输减少。尽管 Sec14 是细胞存活所必需的,但在缺乏 Sec14 功能的细胞中失活编码固醇结合蛋白家族成员的 KES1 基因会导致囊泡运输和细胞生长的恢复。SGA 分析确定了 Kes1 和 Sec14 在调节高尔基体 PI-4-磷酸(PI-4-P)的水平和功能中的作用。SGA 还确定 Sec14 不仅调节反式高尔基体中的囊泡运输,还调节从内体到反式高尔基体的运输。通过比较数据库中的 SGA 筛选,结合遗传和细胞生物学分析,进一步确定受 Kes1 影响的 PI-4-P 池是由 PI 4-激酶 Pik1 产生的。SGA 揭示的 Sec14 和 Kes1 的一个重要生物学作用是协调调节由 Pik1 产生的 Golgi PI-4-P 池,该池对于囊泡进入和离开反式高尔基体的运输是必不可少的。

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