Distinct transcriptional responses elicited by unfolded nuclear or cytoplasmic protein in mammalian cells.
Distinct transcriptional responses elicited by unfolded nuclear or cytoplasmic protein in mammalian cells.
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DOI：
10.7554/elife.07687
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发表时间：
2015-08-28
期刊：
影响因子：
7.7
通讯作者：
Wandless TJ
中科院分区：
文献类型：
--
作者：
Miyazaki Y;Chen LC;Chu BW;Swigut T;Wandless TJ
真核细胞具有防止未折叠和错误折叠蛋白质积累的多种信号通路。其中最主要的是热休克反应（HSR），它被认为是对细胞质和细胞核中未折叠蛋白质的反应。在这项研究中，我们使用称为“不稳定结构域”的工程蛋白进一步探索这一公理，我们用小分子控制其折叠状态。未折叠蛋白在哺乳动物细胞中的突然出现引起了强烈的转录反应，这与HSR和其他已知的响应未折叠蛋白的途径不同。细胞对未折叠蛋白的反应在细胞核和胞质溶胶中是显著不同的，尽管未折叠蛋白在任一隔室中参与p53网络。这种反应在随后的蛋白毒性应激过程中提供交叉保护，表明它是蛋白质质量控制网络的核心组成部分，并且像HSR一样，可能影响人类病理学的起始和进展。http://dx.doi.org/10.7554/eLife.07687.001大多数细胞蛋白质必须折叠成精确的形状才能正确工作。但是，当细胞经历高温和有害化学物质等压力条件时，蛋白质开始错误折叠甚至完全展开。错误折叠的蛋白质可能具有很高的毒性。因此，细胞使用几组不同的分子在通路中一起工作，以检测并重新折叠错误折叠的蛋白质。蛋白质错误折叠主要是在极端的实验条件下研究的，这些条件会导致数百种不同的蛋白质同时错误折叠。2006年，研究人员开发了一种技术，可以用来在折叠和展开状态之间切换蛋白质。宫崎等人-包括参与2006年工作的几位研究人员，已经使用这种技术来研究当单个蛋白质展开时细胞如何反应。未折叠蛋白质的突然出现增加了几个基因的表达。这些基因中的一些是已知途径的一部分，但大多数不知道对蛋白质折叠应激的反应。细胞的反应也不同，这取决于未折叠的蛋白质是在细胞核中还是在胞质溶胶（包围细胞核和其他细胞成分的液体）中产生的。宫崎等人发现，一种分子网络（部分由一种称为p53的蛋白质控制）激活了细胞核或细胞质中对未折叠蛋白质的反应。激活这个网络的细胞也能够更好地保护自己免受进一步的压力。这种新发现的途径可能在监测细胞中蛋白质的质量方面发挥重要作用。下一步涉及识别识别未折叠蛋白质的细胞传感器以及负责增加基因表达的转录因子。随着对这种新反应的更全面了解，将有可能敲除特定的通路以确定它们的作用。DOI：http://dx.doi.org/10.7554/eLife.07687.002网站
Eukaryotic cells possess a variety of signaling pathways that prevent accumulation of unfolded and misfolded proteins. Chief among these is the heat shock response (HSR), which is assumed to respond to unfolded proteins in the cytosol and nucleus alike. In this study, we probe this axiom further using engineered proteins called ‘destabilizing domains’, whose folding state we control with a small molecule. The sudden appearance of unfolded protein in mammalian cells elicits a robust transcriptional response, which is distinct from the HSR and other known pathways that respond to unfolded proteins. The cellular response to unfolded protein is strikingly different in the nucleus and the cytosol, although unfolded protein in either compartment engages the p53 network. This response provides cross-protection during subsequent proteotoxic stress, suggesting that it is a central component of protein quality control networks, and like the HSR, is likely to influence the initiation and progression of human pathologies. DOI: http://dx.doi.org/10.7554/eLife.07687.001 The majority of cellular proteins must be folded into a precise shape to work correctly. But when cells experience stressful conditions such as high temperatures and harmful chemicals, proteins start misfolding or even completely unfold. Misfolded proteins can be highly toxic. As a result, cells use several different groups of molecules that work together in pathways to both detect and then refold incorrectly folded proteins. Protein misfolding has mainly been studied under extreme experimental conditions that cause hundreds of different proteins to misfold at the same time. In 2006, researchers developed a technique that can be used to switch a protein between a folded and an unfolded state. Now, Miyazaki et al.—including several of the researchers involved in the 2006 work—have used this technique to investigate how a cell responds when a single protein unfolds. The sudden appearance of the unfolded protein increased the expression of several genes. Some of these genes are part of known pathways, but the majority were not known to respond to protein-folding stress. The cell also reacts differently depending on whether the unfolded protein is made in the cell nucleus, or the cytosol (the fluid that surrounds the nucleus and other cellular components). Miyazaki et al. discovered that a network of molecules controlled, in part, by a protein called p53 activates the response to unfolded proteins in either the nucleus or the cytosol. Cells that activated this network were also better able to protect themselves from further stress. This newly discovered pathway is likely to play an important role in monitoring the quality of the proteins made in the cell. The next step involves identifying the cellular sensor(s) that recognize the unfolded protein as well as the transcription factors that are responsible for increasing gene expression. With a more complete picture of this new response, it will be possible to knock-out specific pathways to determine their roles. DOI: http://dx.doi.org/10.7554/eLife.07687.002