Transcriptional Repression of ATF4 Gene by CCAAT/Enhancer-binding Protein β (C/EBP β) Differentially Regulates Integrated Stress Response
Transcriptional Repression of ATF4 Gene by CCAAT/Enhancer-binding Protein β (C/EBP β) Differentially Regulates Integrated Stress Response
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DOI：
10.1074/jbc.m112.351783
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发表时间：
2012-06-22
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;Savant, Sudha;Wek, Ronald C.
不同的环境压力会诱导 eIF2 磷酸化（eIF2 与 P 相似），抑制整体蛋白质合成，同时 ATF4 优先翻译。 ATF4 是参与代谢和营养吸收、抗氧化和细胞凋亡调节的基因的转录激活剂。由于ATF4是一个常见的下游靶点，整合了来自不同eIF2激酶的信号及其各自的应激信号，因此与P/ATF4通路类似的eIF2统称为整合应激反应。尽管与 P 类似的 eIF2 会响应许多不同的胁迫而引发翻译控制，但有一些选定的胁迫（例如暴露于 UV 照射）尽管 eIF2 与 P 类似，但不会增加 ATF4 表达。这种 ATF4 表达和与 P 类似的 eIF2 响应 UV 照射的不一致诱导的基本原理是 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，我们证明 C/EBP beta 是紫外线胁迫期间 ATF4 的转录抑制因子。 C/EBP beta 与 ATF4 启动子中的关键元件结合，导致其转录抑制。 C/EBP β 的表达因紫外线应激而增加，C/EBP β 的肝脏富集抑制蛋白 (LIP) 亚型（而非肝脏富集激活蛋白 (LAP) 版本）抑制 ATF4 转录。肝脏富含的抑制蛋白亚型的缺失导致 ATF4 mRNA 水平响应紫外线照射而增加，并随后恢复 ATF4 翻译，从而导致其靶基因的表达增强。这些结果共同说明了与 P 相似的 eIF2 和翻译控制与受替代信号通路调节的转录因子相结合如何指导针对每种环境胁迫专门定制的基因表达程序。
Different environmental stresses induce the phosphorylation of eIF2 (eIF2 similar to 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 similar to P/ATF4 pathway is collectively referred to as the integrated stress response. Although eIF2 similar to 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 similar to P. The rationale for this discordant induction of ATF4 expression and eIF2 similar to 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/EBP beta is a transcriptional repressor of ATF4 during UV stress. C/EBP beta binds to critical elements in the ATF4 promoter, resulting in its transcriptional repression. Expression of C/EBP beta increases in response to UV stress, and the liver-enriched inhibitory protein (LIP) isoform of C/EBP beta, 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 similar to 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.