Regulation of PI4,5P2 synthesis by nuclear-cytoplasmic shuttling of the Mss4 lipid kinase
Regulation of PI4,5P2 synthesis by nuclear-cytoplasmic shuttling of the Mss4 lipid kinase
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DOI：
10.1093/emboj/cdg397
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发表时间：
2003-08-15
期刊：
影响因子：
11.4
通讯作者：
Emr, SD
中科院分区：
文献类型：
--
作者：
Audhya, A;Emr, SD
必需磷脂PI 4，5 P（2）由酵母中高度保守的PI 4 P 5-激酶Mss 4产生。PI 4，5 P（2）的平衡产生和周转对于肌动蛋白细胞骨架的正常组织和细胞活力是重要的。先前的研究表明，多种PI磷酸酶可以调节PI 4，5 P（2）水平。我们报告了一种新的，意想不到的PI 4，5 P（2）稳态的调节机制，由脂质激酶的核质穿梭指导。我们发现，Mss 4是一个磷蛋白，它包含一个功能性的核定位信号（NLS），并可以在细胞质和细胞核之间穿梭。在细胞核中积累Mss 4蛋白的温度条件下的Mss 4细胞表现出PI 4，5 P水平降低（2），肌动蛋白细胞骨架去极化和Mss 4磷酸化阻滞，这表明磷酸化的Mss 4在质膜上起着重要作用。通过分离mss 4突变体的基因剂量依赖性抑制因子，我们确定了Bcp 1，一种富集在细胞核中的蛋白质，它是mss 4核输出所需的，与哺乳动物BRCA 2相互作用蛋白BCCIP相关。总之，这些研究提出了一种新的机制，通过调节细胞核-细胞质穿梭的脂质激酶调节。
The essential phospholipid PI4,5P(2) is generated by a well conserved PI4P 5-kinase, Mss4, in yeast. Balanced production and turnover of PI4,5P(2) is important for normal organization of the actin cytoskeleton and cell viability. Previous studies have shown that multiple PI phosphatases can regulate PI4,5P(2) levels. We report a new, unexpected regulatory mechanism for PI4,5P(2) homeostasis, directed by nuclear-cytoplasmic shuttling of the lipid kinase. We show that Mss4 is a phosphoprotein, which contains a functional nuclear localization signal (NLS) and can shuttle between the cytoplasm and the nucleus. Temperature-conditional mss4 cells that accumulate Mss4 protein in the nucleus exhibit reduced levels of PI4,5P(2), depolarization of the actin cytoskeleton and a block in Mss4 phosphorylation, suggesting an essential role for phosphorylated Mss4 at the plasma membrane. Through the isolation of gene dosage-dependent suppressors of mss4 mutants, we identified Bcp1, a protein enriched in the nucleus, which is required for Mss4 nuclear export and is related to the mammalian BRCA2-interacting protein BCCIP. Together, these studies suggest a new mechanism for lipid kinase regulation through regulated nuclear-cytoplasmic shuttling.