PI3K-mTORC1 Attenuates Stress Response by Inhibiting Cap-independent Hsp70 Translation
PI3K-mTORC1 Attenuates Stress Response by Inhibiting Cap-independent Hsp70 Translation
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DOI：
10.1074/jbc.m110.172882
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发表时间：
2011-02-25
影响因子：
4.8
通讯作者：
Qian, Shu-Bing
中科院分区：
文献类型：
--
作者：
Sun, Jun;Conn, Crystal S.;Qian, Shu-Bing
蛋白质合成是一个关键的调节细胞过程，连接营养物质的可用性和生物体的生长。人们早就知道，一些细胞蛋白质在整体翻译严重受损的条件下继续合成。一个突出的例子是热休克蛋白（Hsps）在应激条件下的选择性翻译。虽然热休克蛋白基因的转录调控已被很好地建立，既没有具体的免疫促进功能，也没有翻译机的调节机制已被明确定义。在这里，我们表明，压力诱导的优先翻译Hsp 70 mRNA的负调控PI 3 K-mTORC 1信号。尽管转录上调，翻译热休克蛋白70 mRNA是缺乏结节性硬化症复合体2的细胞。相反，Hsp 70合成在减少的PI 3 K-mTORC 1信号传导下增强。我们发现Hsp 70 mRNA的5'非翻译区不具有典型的内部核糖体进入位点的特征，但有助于帽非依赖性翻译。我们的研究结果暗示了持续的PI 3 K-mTORC 1信号传导如何通过减弱应激抵抗力来促进年龄相关病理学的发展的合理机制。
Protein synthesis is a key regulated cellular process that links nutrient availability and organismal growth. It has long been known that some cellular proteins continue to be synthesized under conditions where global translation is severely compromised. One prominent example is the selective translation of heat shock proteins (Hsps) under stress conditions. Although the transcriptional regulation of Hsp genes has been well established, neither the specific translation-promoting features nor the regulatory mechanism of the translation machinery have been clearly defined. Here we show that the stress-induced preferential translation of Hsp70 mRNA is negatively regulated by PI3K-mTORC1 signaling. Despite the transcriptional up-regulation, the translation of Hsp70 mRNA is deficient in cells lacking tuberous sclerosis complex 2. Conversely, Hsp70 synthesis is enhanced under the reduced PI3K-mTORC1 signaling. We found that the 5' UTR of Hsp70 mRNA contributes to cap-independent translation without exhibiting typical features of internal ribosome entry site. Our findings imply a plausible mechanism for how persistent PI3K-mTORC1 signaling favors the development of age-related pathologies by attenuating stress resistance.