Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
J Biol Chem. 2012 Jun 22;287(26):21936-49. doi: 10.1074/jbc.M112.351783. Epub 2012 May 3.
Different environmental stresses induce the phosphorylation of eIF2 (eIF2∼P), repressing global protein synthesis coincident with preferential translation of ATF4. ATF4 is a transcriptional activator of genes involved in metabolism and nutrient uptake, antioxidation, and regulation of apoptosis. Because ATF4 is a common downstream target that integrates signaling from different eIF2 kinases and their respective stress signals, the eIF2∼P/ATF4 pathway is collectively referred to as the integrated stress response. Although eIF2∼P elicits translational control in response to many different stresses, there are selected stresses, such as exposure to UV irradiation, that do not increase ATF4 expression despite robust eIF2∼P. The rationale for this discordant induction of ATF4 expression and eIF2∼P in response to UV irradiation is that transcription of ATF4 is repressed, and therefore ATF4 mRNA is not available for preferential translation. In this study, we show that C/EBPβ is a transcriptional repressor of ATF4 during UV stress. C/EBPβ binds to critical elements in the ATF4 promoter, resulting in its transcriptional repression. Expression of C/EBPβ increases in response to UV stress, and the liver-enriched inhibitory protein (LIP) isoform of C/EBPβ, but not the liver-enriched activating protein (LAP) version, represses ATF4 transcription. Loss of the liver-enriched inhibitory protein isoform results in increased ATF4 mRNA levels in response to UV irradiation and subsequent recovery of ATF4 translation, leading to enhanced expression of its target genes. Together these results illustrate how eIF2∼P and translational control combined with transcription factors regulated by alternative signaling pathways can direct programs of gene expression that are specifically tailored to each environmental stress.
不同的环境应激诱导 eIF2 的磷酸化（eIF2∼P），与 ATF4 的优先翻译同时抑制全局蛋白质合成。ATF4 是参与代谢和营养摄取、抗氧化和凋亡调节的基因的转录激活物。由于 ATF4 是整合来自不同 eIF2 激酶及其各自应激信号的信号的共同下游靶标，因此 eIF2∼P/ATF4 途径被统称为综合应激反应。尽管 eIF2∼P 在响应许多不同应激时引发翻译控制，但存在一些选定的应激，例如暴露于紫外线照射下，尽管 eIF2∼P 强烈增加，但不会增加 ATF4 表达。这种在紫外线照射下 ATF4 表达和 eIF2∼P 诱导的不和谐的原因是 ATF4 的转录受到抑制，因此 ATF4 mRNA 不可用于优先翻译。在这项研究中，我们表明 C/EBPβ 在紫外线应激期间是 ATF4 的转录抑制剂。C/EBPβ 结合到 ATF4 启动子的关键元件上，导致其转录抑制。C/EBPβ 的表达响应于紫外线应激而增加，并且 C/EBPβ 的肝丰富抑制蛋白（LIP）同工型而不是肝丰富激活蛋白（LAP）版本抑制 ATF4 转录。肝丰富抑制蛋白同工型的缺失导致紫外线照射后 ATF4 mRNA 水平增加，随后 ATF4 翻译恢复，导致其靶基因表达增强。这些结果共同说明了 eIF2∼P 和翻译控制如何与受替代信号通路调节的转录因子结合，从而指导针对每种环境应激的专门基因表达程序。
