Hypoxia controls plasma membrane targeting of polarity proteins by dynamic turnover of PI4P and PI(4,5)P2.
Hypoxia controls plasma membrane targeting of polarity proteins by dynamic turnover of PI4P and PI(4,5)P2.
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DOI：
10.7554/elife.79582
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发表时间：
2022-06-09
期刊：
影响因子：
7.7
通讯作者：
Hong, Yang
中科院分区：
文献类型：
--
作者：
Lu, Juan;Dong, Wei;Hammond, Gerald R.;Hong, Yang
磷脂酰肌醇4-磷酸（PI 4P）和磷脂酰肌醇4，5-二磷酸（PIP 2）是决定质膜（PM）身份并调节其中许多关键生物事件的关键磷酸肌醇。迄今为止，调节PM PI 4P和PIP 2响应于各种生理条件和应激的稳态和动态周转的机制仍有待完全阐明。在这里，我们报告说，在果蝇缺氧诱导急性和可逆的耗尽PM PI 4P和PIP 2，严重破坏多个多元极性蛋白的静电PM靶向。遗传编码的ATP传感器证实，缺氧诱导细胞ATP水平的急性和可逆的降低，其显示出与培养细胞中PM PI 4P和PIP 2水平的强实时相关性。通过将遗传操作与定量成像分析相结合，我们表明，在常氧和缺氧条件下，PI 4 K III α以及Rbo/EFR 3和TTC 7是将PI 4 K III α靶向PM所必需的，是维持PM PI 4 P和PIP 2的稳态和动态转换所必需的。我们的研究结果表明，在由缺氧，ATP抑制和可能的缺血触发的能量应激的细胞中，PM PI 4P和PIP 2的急剧周转可能对许多细胞过程产生深远的影响，包括静电PM靶向许多多元蛋白。
Phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol 4,5-biphosphate (PIP2) are key phosphoinositides that determine the identity of the plasma membrane (PM) and regulate numerous key biological events there. To date, mechanisms regulating the homeostasis and dynamic turnover of PM PI4P and PIP2 in response to various physiological conditions and stresses remain to be fully elucidated. Here, we report that hypoxia in Drosophila induces acute and reversible depletion of PM PI4P and PIP2 that severely disrupts the electrostatic PM targeting of multiple polybasic polarity proteins. Genetically encoded ATP sensors confirmed that hypoxia induces acute and reversible reduction of cellular ATP levels which showed a strong real-time correlation with the levels of PM PI4P and PIP2 in cultured cells. By combining genetic manipulations with quantitative imaging assays we showed that PI4KIIIα, as well as Rbo/EFR3 and TTC7 that are essential for targeting PI4KIIIα to PM, are required for maintaining the homeostasis and dynamic turnover of PM PI4P and PIP2 under normoxia and hypoxia. Our results revealed that in cells challenged by energetic stresses triggered by hypoxia, ATP inhibition and possibly ischemia, dramatic turnover of PM PI4P and PIP2 could have profound impact on many cellular processes including electrostatic PM targeting of numerous polybasic proteins.