Phosphatidylinositol 4,5-Bisphosphate Homeostasis Regulated by Nir2 and Nir3 Proteins at Endoplasmic Reticulum-Plasma Membrane Junctions
Phosphatidylinositol 4,5-Bisphosphate Homeostasis Regulated by Nir2 and Nir3 Proteins at Endoplasmic Reticulum-Plasma Membrane Junctions
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DOI：
10.1074/jbc.m114.621375
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发表时间：
2015-06-05
影响因子：
4.8
通讯作者：
Liou, Jen
中科院分区：
文献类型：
--
作者：
Chang, Chi-Lun;Liou, Jen
磷脂酰肌醇（PI）4，5-二磷酸（PIP 2）在质膜（PM）上组成性地控制许多细胞功能，并且其通过受体刺激的水解控制细胞信号传导。PI转移蛋白Nir 2对于在受体诱导的水解之后补充PM PIP 2是必不可少的，但是该过程的关键机制方面仍然难以捉摸。在这里，我们证明了PI在内质网（ER）的膜上是由Nir 2介导的PM PIP 2的快速补充所必需的。Nir 2检测PIP 2水解并通过与磷脂酸结合易位至ER-PM连接处。具有不同的磷脂酸结合能力和PI转运蛋白活性，Nir 2和其同系物Nir 3分别在强烈的受体刺激和静息状态下差异调节细胞中的PIP 2稳态。我们的研究表明，Nir 2和Nir 3协同工作，以实现基于PM PIP 2消耗的不同水平的反馈，并在ER-PM连接处起作用，以介导ER和PM之间的非囊泡脂质转运。
Phosphatidylinositol (PI) 4,5-bisphosphate (PIP2) at the plasma membrane (PM) constitutively controls many cellular functions, and its hydrolysis via receptor stimulation governs cell signaling. The PI transfer protein Nir2 is essential for replenishing PM PIP2 following receptor-induced hydrolysis, but key mechanistic aspects of this process remain elusive. Here, we demonstrate that PI at the membrane of the endoplasmic reticulum (ER) is required for the rapid replenishment of PM PIP2 mediated by Nir2. Nir2 detects PIP2 hydrolysis and translocates to ER-PM junctions via binding to phosphatidic acid. With distinct phosphatidic acid binding abilities and PI transfer protein activities, Nir2 and its homolog Nir3 differentially regulate PIP2 homeostasis in cells during intense receptor stimulation and in the resting state, respectively. Our study reveals that Nir2 and Nir3 work in tandem to achieve different levels of feedback based on the consumption of PM PIP2 and function at ER-PM junctions to mediate nonvesicular lipid transport between the ER and the PM.