Human protein phosphatase PP6 regulatory subunits provide Sit4-dependent and rapamycin-sensitive sap function in Saccharomyces cerevisiae.
Human protein phosphatase PP6 regulatory subunits provide Sit4-dependent and rapamycin-sensitive sap function in Saccharomyces cerevisiae.
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DOI：
10.1371/journal.pone.0006331
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发表时间：
2009-07-21
期刊：
影响因子：
3.7
通讯作者：
Cardenas ME
中科院分区：
文献类型：
--
作者：
Morales-Johansson H;Puria R;Brautigan DL;Cardenas ME
在芽生酵母中，蛋白磷酸酶Sit4和4个相关蛋白(Sap4、Sap155、Sap185和Sap190)介导G1至S细胞周期进程和一系列受雷帕霉素TOR信号转导靶标控制的信号事件。Sit4和SAP蛋白普遍保守，它们的人类同源蛋白PP6和三个PP6R蛋白与它们的酵母同源蛋白具有显著的序列相似性。然而，对PP6和PP6R蛋白在哺乳动物细胞中的功能知之甚少。在这里，我们证明了当在酵母细胞中表达时，人PP6R蛋白与Sit4物理上相互作用。值得注意的是，PP6R2和PP6R3的表达而不是PP6R1的表达挽救了缺乏所有四种SAP的酵母细胞的生长缺陷和雷帕霉素敏感，这些作用需要Sit4。此外，PP6R2和PP6R3促进了细胞周期蛋白G1基因的表达和DNA合成，部分消除了酵母四重汁液突变株的G1细胞周期延迟和发芽缺陷。相比之下，人类PP6R蛋白仅适度支持氮分解代谢基因的表达，并且无法恢复四重汁液突变株中eIF2α的正常磷酸化水平。这些结果表明，人类PP6相关蛋白能够在酵母细胞的异源环境中提供不同的雷帕霉素敏感和Sit4依赖的SAP功能。我们推测，人类SAP可能在后生动物的mTORC1-PP6信号事件中发挥类似的作用。
In the budding yeast Saccharomyces cerevisiae the protein phosphatase Sit4 and four associated proteins (Sap4, Sap155, Sap185, and Sap190) mediate G1 to S cell cycle progression and a number of signaling events controlled by the target of rapamycin TOR signaling cascade. Sit4 and the Sap proteins are ubiquitously conserved and their human orthologs, PP6 and three PP6R proteins, share significant sequence identity with their yeast counterparts. However, relatively little is known about the functions of the PP6 and PP6R proteins in mammalian cells. Here we demonstrate that the human PP6R proteins physically interact with Sit4 when expressed in yeast cells. Remarkably, expression of PP6R2 and PP6R3 but not expression of PP6R1 rescues the growth defect and rapamycin hypersensitivity of yeast cells lacking all four Saps, and these effects require Sit4. Moreover, PP6R2 and PP6R3 enhance cyclin G1 gene expression and DNA synthesis, and partially abrogate the G1 cell cycle delay and the budding defect of the yeast quadruple sap mutant strain. In contrast, the human PP6R proteins only modestly support nitrogen catabolite gene expression and are unable to restore normal levels of eIF2α phosphorylation in the quadruple sap mutant strain. These results illustrate that the human PP6-associated proteins are capable of providing distinct rapamycin-sensitive and Sit4-dependent Sap functions in the heterologous context of the yeast cell. We hypothesize that the human Saps may play analogous roles in mTORC1-PP6 signaling events in metazoans.
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