Whi2p links nutritional sensing to actin-dependent Ras-cAMP-PKA regulation and apoptosis in yeast
Whi2p links nutritional sensing to actin-dependent Ras-cAMP-PKA regulation and apoptosis in yeast
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DOI：
10.1242/jcs.042424
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发表时间：
2009-03-01
影响因子：
4
通讯作者：
Gourlay, Campbell W.
中科院分区：
文献类型：
--
作者：
Leadsham, Jane E.;Miller, Katherine;Gourlay, Campbell W.
阐明真核细胞协调环境信号与细胞内“命运”决定（如细胞凋亡）的机制仍然是细胞生物学家面临的重要挑战之一。最近发现，肌动蛋白细胞骨架的动态特性是细胞外刺激感觉与调节程序性细胞死亡的信号机制联系的重要因素。在酵母中，肌动蛋白已被证明通过促进Ras-cAMP-PKA通路活性的关闭，在细胞在面对营养耗尽时准备自己静止时的凋亡调节中发挥作用。在这里，我们证明了wh2p功能的丧失，一种在营养应激条件下影响细胞周期退出的蛋白质，导致酵母细胞死亡，表现出肌动蛋白介导的细胞凋亡的特征。我们发现，肌动蛋白介导的细胞凋亡是Delta wh2细胞中Ras-cAMP-PKA活性不适当的结果。缺乏wh2p功能的细胞在线粒体中表现出激活的Ras2的异常积累，以响应营养消耗。这项研究提供了证据，证明野生型细胞中cAMP-PKA信号活性的关闭涉及依赖于whi2p的Ras2p靶向液泡进行蛋白水解。我们也首次证明了cAMP-PKA信号的wh2p依赖性调控在酵母菌落分化中发挥生理作用，促进了不同细胞死亡区域的细化。
Elucidating the mechanisms by which eukaryotic cells coordinate environmental signals with intracellular 'fate' decisions, such as apoptosis, remains one of the important challenges facing cell biologists. It has recently emerged that the dynamic nature of the actin cytoskeleton is an important factor in the linkage of sensation of extracellular stimuli to signalling mechanisms that regulate programmed cell death. In yeast, actin has been shown to play a role in the regulation of apoptosis as cells prepare themselves for quiescence in the face of nutritional exhaustion, by facilitating the shutdown of Ras-cAMP-PKA pathway activity. Here, we demonstrate that the loss of Whi2p function, a protein known to influence cell cycle exit under conditions of nutritional stress, leads to cell death in yeast that displays the hallmarks of actin-mediated apoptosis. We show that actin-mediated apoptosis occurs as a result of inappropriate Ras-cAMP-PKA activity in Delta whi2 cells. Cells lacking Whi2p function exhibit an aberrant accumulation of activated Ras2 at the mitochondria in response to nutritional depletion. This study provides evidence that the shutdown of cAMP-PKA signalling activity in wild-type cells involves Whi2p-dependent targeting of Ras2p to the vacuole for proteolysis. We also demonstrate for the first time that Whi2p-dependent regulation of cAMP-PKA signalling plays a physiological role in the differentiation of yeast colonies by facilitating elaboration of distinct zones of cell death.