Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate
Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate
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DOI：
10.1038/nature12360
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发表时间：
2013-07-11
期刊：
影响因子：
64.8
通讯作者：
Haucke, Volker
中科院分区：
文献类型：
--
作者：
Posor, York;Eichhorn-Gruenig, Marielle;Haucke, Volker
肌醇磷脂在细胞生理学中起着至关重要的作用，从细胞信号转导到膜运输(1，2)。在七种真核磷脂酰肌醇中，研究得最多的是磷脂酰肌醇-4，5-二磷酸(PI(4，5)P-2)，它集中在质膜上，除了其他功能外，它还是胞内网状蛋白包裹的凹坑成核所必需的(3-6)。除PI(4，5)P-2外，没有其他磷脂酰肌醇参与胞内蛋白介导的内吞作用，而随后的内吞途径的内体阶段主要由磷脂酰肌醇-3-磷酸(PI(3)P)(7)主导。磷脂酰肌醇是如何从PI(4，5)P-2阳性的胞内中间体转化为含有PI(3)P的内涵体的，目前尚不清楚。在这里，我们证明了磷脂酰肌醇-3-二磷酸(PI(3，4)P-2)由第二类磷脂酰肌醇-3-激酶C2α(PI(3)K C2α)形成，在时空上控制了网状蛋白介导的内吞作用。PI(3，4)P-2或PI(3)K C2α的缺失会损害晚期笼状蛋白包衣小孔在分裂前的成熟。PI(3)K C2α需要PI(3，4)P-2的定时形成，以选择性地在晚期内吞中间体富集杆状结构域蛋白SNX9。这些发现为PI(3，4)P-2在内吞作用中的作用提供了一个机制框架，并揭示了PI(3，4)P-2在中央细胞生理过程中的一个新的离散功能。
Phosphoinositides serve crucial roles in cell physiology, ranging from cell signalling to membrane traffic(1,2). Among the seven eukaryotic phosphoinositides the best studied species is phosphatidylinositol-4,5-bisphosphate (PI(4,5)P-2), which is concentrated at the plasma membrane where, among other functions, it is required for the nucleation of endocytic clathrin-coated pits(3-6). No phosphatidylinositol other than PI(4,5)P-2 has been implicated in clathrin-mediated endocytosis, whereas the subsequent endosomal stages of the endocytic pathway are dominated by phosphatidylinositol-3-phosphates(PI(3)P)(7). How phosphatidylinositol conversion from PI(4,5)P-2-positive endocytic intermediates to PI(3)P-containing endosomes is achieved is unclear. Here we show that formation of phosphatidylinositol-3,4-bisphosphate (PI(3,4)P-2) by class II phosphatidylinositol-3-kinase C2 alpha (PI(3) K C2 alpha) spatiotemporally controls clathrin-mediated endocytosis. Depletion of PI(3,4)P-2 or PI(3)K C2 alpha impairs the maturation of late-stage clathrin-coated pits before fission. Timed formation of PI(3,4)P-2 by PI(3)K C2 alpha is required for selective enrichment of the BAR domain protein SNX9 at late-stage endocytic intermediates. These findings provide a mechanistic framework for the role of PI(3,4)P-2 in endocytosis and unravel a novel discrete function of PI(3,4)P-2 in a central cell physiological process.