Both Transcriptional Regulation and Translational Control of ATF4 Are Central to the Integrated Stress Response
Both Transcriptional Regulation and Translational Control of ATF4 Are Central to the Integrated Stress Response
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DOI：
10.1074/jbc.m110.167213
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发表时间：
2010-10-22
影响因子：
4.8
通讯作者：
Wek, Ronald C.
中科院分区：
文献类型：
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作者：
Dey, Souvik;Baird, Thomas D.;Wek, Ronald C.
为了应对不同的环境胁迫，eIF2 的磷酸化（eIF2 与 P 类似）会抑制全局翻译，这与 ATF4 的优先翻译一致。 ATF4 是整合应激反应的转录激活剂，整合应激反应是一种基因表达程序，涉及代谢、营养吸收、抗氧化以及其他转录因子（例如可诱导细胞凋亡的 CHOP/GADD153）的激活。尽管 eIF2-P 会针对许多不同的应激安排引发翻译控制，但有一些特定的应激（例如暴露于紫外线照射）不会增加 ATF4 的表达，尽管 eIF2 与 P 相似，但 eIF2-P 具有强大的表达能力。在这项研究中，我们探讨了在不同应激条件下，ATF4 响应与 P 相似的 eIF2 的可变表达的潜在机制，以及省略增强的 ATF4 功能的生物学意义。我们发现除了翻译控制之外，ATF4 表达还受到转录调控。内质网应激等应激条件诱导 ATF4 的转录和翻译，这共同增强了 ATF4 及其靶基因的表达，以响应类似于 P 的 eIF2。相比之下，UV 照射抑制 ATF4 转录，从而减少了在类似于 P 的 eIF2 期间可用于翻译的 ATF4 mRNA。类似于 P 的 eIF2 增强了细胞对紫外线照射的存活率。然而，ATF4 及其靶基因 CHOP 的强制表达会导致对紫外线照射的敏感性增加。这种转录调控和翻译控制的结合使得 eIF2 激酶途径能够选择性地抑制或激活优先翻译的关键调控基因，从而提供综合应激反应多功能性来指导转录组，这对于维持应激修复和细胞凋亡之间的平衡至关重要。
In response to different environmental stresses, phosphorylation of eIF2 (eIF2 similar to P) represses global translation coincident with preferential translation of ATF4. ATF4 is a transcriptional activator of the integrated stress response, a program of gene expression involved in metabolism, nutrient uptake, anti-oxidation, and the activation of additional transcription factors, such as CHOP/GADD153, that can induce apoptosis. Although eIF2-P elicits translational control in response to many different stress arrangements, there are selected stresses, such as exposure to UV irradiation, that do not increase ATF4 expression despite robust eIF2 similar to P. In this study we addressed the underlying mechanism for variable expression of ATF4 in response to eIF2 similar to P during different stress conditions and the biological significance of omission of enhanced ATF4 function. We show that in addition to translational control, ATF4 expression is subject to transcriptional regulation. Stress conditions such as endoplasmic reticulum stress induce both transcription and translation of ATF4, which together enhance expression of ATF4 and its target genes in response to eIF2 similar to P. By contrast, UV irradiation represses ATF4 transcription, which diminishes ATF4 mRNA available for translation during eIF2 similar to P. eIF2 similar to P enhances cell survival in response to UV irradiation. However, forced expression of ATF4 and its target gene CHOP leads to increased sensitivity to UV irradiation. This combination of transcriptional regulation and translational control allows the eIF2 kinase pathway to selectively repress or activate key regulatory genes subject to preferential translation, providing the integrated stress response versatility to direct the transcriptome that is essential for maintaining the balance between stress remediation and apoptosis.