Alteration of the nuclear pore complex in Ca2+-mediated cell death
Alteration of the nuclear pore complex in Ca2+-mediated cell death
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DOI：
10.1038/cdd.2009.112
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发表时间：
2010-01-01
影响因子：
12.4
通讯作者：
Nicotera, P.
中科院分区：
文献类型：
--
作者：
Bano, D.;Dinsdale, D.;Nicotera, P.
在降解酶分解细胞结构之前，细胞死亡需要细胞内协调的信号传导。尽管涉及线粒体、内质网和质膜的死亡信号级联已被广泛表征，但只有少数研究考察了神经元死亡过程中核孔复合物（NPC）的功能和结构变化。本研究表明，在兴奋性毒性神经元变性过程中，钙蛋白在核膜上重新分布，并介导NPC成分的降解，导致核膜通透性改变。在初级解离的神经元中，同时记录胞质[Ca2+]和荧光蛋白的定位表明，Ca2+过载的开始表明小报告分子在核膜上的扩散逐渐增加。随后，calpain介导的核孔通透性改变使大蛋白在细胞核中积累。此外，在秀丽隐杆线虫（Caenorhabditis elegans）的兴奋性毒性神经元变性模型中，我们发现了类似的核变化和荧光探针在垂死神经元核膜上的重新分布。我们的研究结果强烈表明，核屏障的泄漏增加影响核胞质运输，改变蛋白质在核膜上的定位，并可能参与Ca2+依赖性细胞死亡，包括缺血性神经元死亡。细胞死亡与分化（2010）17,119-133；doi: 10.1038 / cdd.2009.112;2009年8月28日在线发布
Cell death requires coordinated intracellular signalling before disassembly of cell architecture by degradative enzymes. Although the death signalling cascades that involve the mitochondria, the ER and the plasma membrane have been extensively characterized, only a handful of studies have examined the functional and structural alterations of the nuclear pore complex (NPC) during neuronal death. Here, we show that during excitotoxic neuronal degeneration calpains redistributed across the nuclear envelope and mediated the degradation of NPC components causing altered permeability of the nuclear membrane. In primary dissociated neurons, simultaneous recording of cytosolic [Ca2+] and localization of fluorescent proteins showed that the onset of Ca2+ overload signalled a progressive increase in the diffusion of small reporter molecules across the nuclear envelope. Later, calpain-mediated changes in nuclear pore permeability allowed accumulation of large proteins in the nucleus. Further, in a model of excitotoxic neuronal degeneration in Caenorhabditis elegans, we found similar nuclear changes and redistribution of fluorescent probes across the nuclear membrane in dying neurons. Our findings strongly suggest that increased leakiness of the nuclear barrier affects nucleocytoplasmic transport, alters the localization of proteins across the nuclear envelope and it is likely to be involved in Ca2+-dependent cell death, including ischemic neuronal demise. Cell Death and Differentiation (2010) 17, 119-133; doi:10.1038/cdd.2009.112; published online 28 August 2009