Identification of an upstream regulatory pathway controlling actin-mediated apoptosis in yeast
Identification of an upstream regulatory pathway controlling actin-mediated apoptosis in yeast
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DOI：
10.1242/jcs.02337
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发表时间：
2005-05-15
影响因子：
4
通讯作者：
Ayscough, KR
中科院分区：
文献类型：
--
作者：
Gourlay, CW;Ayscough, KR
已知活性氧（ROS）的积累有助于细胞寿命的缩短以及它们在诸如阿尔茨海默氏症和组织缺血的疾病中的退化。因此，阐明调节细胞氧化应激的途径是重要的。我们以前已经表明，肌动蛋白动力学可以影响酵母细胞上的氧化应激负担，从而影响其潜在的寿命。为了进一步阐明肌动蛋白动力学和氧化应激之间的联系，我们试图确定这一过程的监管机构。肌动蛋白调节蛋白Sla 1 p和End 3 p在维持皮质斑块中F-肌动蛋白的快速周转中是重要的。我们发现，细胞表达突变形式的Sla 1 p或缺乏End 3 p显示凋亡的标志物，如去极化线粒体膜和活性氧水平升高。泛素连接酶RSP 5的过表达可以通过将Sla 1 p靶向皮质并恢复肌动蛋白重塑能力来减轻在缺乏End 3 p的细胞中观察到的氧化应激表型。我们还表明，PDE 2的过度表达，Ras/cAMP途径的负调节拯救肌动蛋白动力学，降低氧化应激敏感性和恢复活力在三角洲end 3细胞。我们的数据表明，第一次，肌动蛋白调节和cAMP信号调节酵母细胞凋亡之间存在生理联系。
The build up of reactive oxygen species (ROS) is known to contribute to a reduction in the lifespan of a cell and to their degeneration in diseases such as Alzheimer's and tissue ischaemia. It is therefore important to elucidate pathways that regulate cellular oxidative stress. We have previously shown that actin dynamics can affect the oxidative-stress burden on a yeast cell and thereby its potential lifespan. To elucidate further the connection between actin dynamics and oxidative stress, we sought to identify regulators of this process. The actin regulatory proteins Sla1p and End3p are important in maintaining a rapid turnover of F-actin in cortical patches. We show that cells expressing a mutated form of Sla1p or lacking End3p display markers of apoptosis such as depolarized mitochondrial membranes and elevated levels of reactive oxygen species. Overexpression of the ubiquitin ligase RSP5 can alleviate the oxidative-stress phenotype observed in cells lacking End3p by targeting Sla1p to the cortex and restoring actin remodelling capability. We also demonstrate that overexpression of PDE2, a negative regulator of the Ras/cAMP pathway rescues actin dynamics, reduces oxidative stress sensitivity and restores viability in Delta end3 cells. Our data suggest, for the first time, that a physiological link exists between actin regulation and cAMP signalling that regulates apoptosis in yeast.