The translation elongation factor eEF1A1 couples transcription to translation during heat shock response.
The translation elongation factor eEF1A1 couples transcription to translation during heat shock response.
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DOI：
10.7554/elife.03164
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发表时间：
2014-09-16
期刊：
影响因子：
7.7
通讯作者：
Nudler E
中科院分区：
文献类型：
--
作者：
Vera M;Pani B;Griffiths LA;Muchardt C;Abbott CM;Singer RH;Nudler E
翻译延伸因子 eEF1A 在蛋白质合成中具有明确的作用。在这项研究中，我们证明了 eEF1A 的新作用：它参与哺乳动物细胞从转录到翻译的热休克反应 (HSR) 的整个过程。应激时，eEF1A 的亚型 1 通过将主调节因子 HSF1 募集至其启动子，快速激活 HSP70 的转录。然后，eEF1A1 与延长 RNA 聚合酶 II 和 HSP70 mRNA 的 3'UTR 结合，使其稳定并促进其从细胞核转运至活性核糖体。 eEF1A1 耗尽的细胞表现出严重受损的 HSR 和耐热性受损。相反，eEF1A 的组织特异性亚型 2 不支持 HSR。通过根据翻译需要调整转录产量，eEF1A1 使 HSR 快速、稳健且具有高度选择性；因此，对于从神经变性到癌症等与蛋白质稳态破坏相关的多种疾病来说，它是一个有吸引力的治疗靶点。 DOI：http://dx.doi.org/10.7554/eLife.03164.001 活细胞必须能够承受环境的变化。例如，如果温度突然升高（这可能会损坏蛋白质或其他分子），大多数细胞都会做出“热休克反应”。在人类和其他哺乳动物中，一种称为热休克因子 1 的蛋白质会触发大量热休克蛋白的产生，从而保护细胞免受高温的有害影响。大多数热休克蛋白通过结合并稳定细胞中的其他分子来保护细胞。这可以防止这些分子被损坏或聚集，并允许它们继续正常发挥作用。一种名为 eEF1A1 的蛋白质参与蛋白质生产的最后阶段，并且在热休克反应期间还增强热休克因子 1 的功能。为了制造蛋白质，一种称为 RNA 聚合酶的酶将细胞核中的 DNA 转录成信使 RNA 分子，然后该分子离开细胞核并与核糖体结合。然后，这个分子机器通过将称为氨基酸的各个构建块以正确的顺序连接在一起，将信使 RNA 序列翻译成蛋白质。与其他延伸因子一样，eEF1A1 有助于选择与信使 RNA 模板序列相匹配的氨基酸。然而，目前尚不清楚 eEF1A1 如何在热休克反应期间帮助保护细胞。努德勒等人。现在，我们已经对来自人类和小鼠的细胞进行了改造，使其产生的 eEF1A1 蛋白含量比正常细胞要少。这些细胞有足够的这种蛋白质来支持它们在正常条件下的生长和发育，但不足以在热休克反应期间提供帮助。当这些细胞遭受温度突然升高时，它们无法产生足够量的主要热休克蛋白。转录编码这些热休克蛋白的基因需要热休克因子 1，Nudler 等人。发现 eEF1A1 必须与热休克因子 1 结合，然后与移动的 RNA 聚合酶结合，这些基因才能有效转录。此外，eEF1A1 蛋白被证明可以结合并稳定热休克蛋白的信使 RNA，并帮助它们从细胞核输出并与核糖体结合。这些新发现的 eEF1A1 在热休克反应过程中的作用凸显了这种延伸因子作为治疗蛋白质折叠出错的疾病（例如阿尔茨海默病或帕金森病）的有前途的药物靶点。在成人中，神经元不能产生足够的 eEF1A1，Nudler 等人。表明使这些细胞产生更多这种蛋白质可能有助于治疗一系列神经退行性疾病。 DOI：http://dx.doi.org/10.7554/eLife.03164.002
Translation elongation factor eEF1A has a well-defined role in protein synthesis. In this study, we demonstrate a new role for eEF1A: it participates in the entire process of the heat shock response (HSR) in mammalian cells from transcription through translation. Upon stress, isoform 1 of eEF1A rapidly activates transcription of HSP70 by recruiting the master regulator HSF1 to its promoter. eEF1A1 then associates with elongating RNA polymerase II and the 3′UTR of HSP70 mRNA, stabilizing it and facilitating its transport from the nucleus to active ribosomes. eEF1A1-depleted cells exhibit severely impaired HSR and compromised thermotolerance. In contrast, tissue-specific isoform 2 of eEF1A does not support HSR. By adjusting transcriptional yield to translational needs, eEF1A1 renders HSR rapid, robust, and highly selective; thus, representing an attractive therapeutic target for numerous conditions associated with disrupted protein homeostasis, ranging from neurodegeneration to cancer. DOI: http://dx.doi.org/10.7554/eLife.03164.001 Living cells must be able to withstand changes in the environment. For example, if there is a sudden increase in temperature—which could damage proteins or other molecules—most cells can respond with the ‘heat shock response’. In humans and other mammals, a single protein called heat shock factor 1 triggers the production of numerous heat shock proteins that protect the cell from the detrimental effects of high temperatures. Most heat shock proteins protect cells by binding to, and stabilizing, other molecules in the cell; this prevents these molecules from being damaged or from aggregating and allows them to continue to function as normal. A protein called eEF1A1 is involved in the final stages of protein production and also enhances the function of heat shock factor 1 during the heat shock response. To make a protein, an enzyme called RNA polymerase transcribes DNA in the nucleus of the cell into a messenger RNA molecule that then exits the nucleus and binds to a ribosome. This molecular machine then translates the messenger RNA sequence into a protein by joining together individual building blocks called amino acids in the correct order. Like other elongation factors, eEF1A1 helps to select the amino acids that match the sequence of the messenger RNA template. However, it was unclear how eEF1A1 helped to protect cells during the heat shock response. Nudler et al. have now engineered cells—from humans and mice—that make less of the eEF1A1 protein than normal. These cells had enough of this protein to support their growth and development under normal conditions, but not enough to help during the heat shock response. When these cells are subjected to a sudden increase in temperature, they fail to produce a sufficient amount of major heat shock proteins. Heat shock factor 1 is needed to transcribe the genes that encode these heat shock proteins, and Nudler et al. found that eEF1A1 must bind to heat shock factor 1 and then to a moving RNA polymerase for these genes to be transcribed efficiently. Moreover, the eEF1A1 protein was shown to bind to and stabilize the heat shock proteins' messenger RNAs, and aid their export from the nucleus and their binding to the ribosome. These newly discovered roles for eEF1A1 during the heat shock response highlight this elongation factor as a promising drug target for treating diseases where protein folding goes awry, for example in Alzheimer's or Parkinson's disease. In adults, neurons do not make enough eEF1A1, and Nudler et al. suggest that enabling these cells to make more of this protein could help to treat a range of neurodegenerative conditions. DOI: http://dx.doi.org/10.7554/eLife.03164.002