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Translational Repression Protects Human Keratinocytes from UVB-Induced Apoptosis through a Discordant eIF2 Kinase Stress Response

机译:翻译抑制通过不一致的eIF2激酶应激反应保护人类角质形成细胞免受UVB诱导的凋亡。

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摘要

This study delineates the mechanisms by which UVB regulates protein synthesis in human keratinocytes and the importance of translational control in cell survival. Translation initiation is regulated by phosphorylation of eukaryotic initiation factor 2 (eIF2-P) that causes decreased global protein synthesis coincident with enhanced translation of selected stress-related transcripts, such as activating transcription factor 4 (ATF4). ATF4 is a transcriptional activator of the integrated stress response (ISR) that has cytoprotective functions as well as apoptotic signals through the downstream transcriptional regulator C/EBP homologous protein (CHOP; GADD153/DDIT3). We determined that UVB irradiation is a potent inducer of eIF2-P in keratinocytes, leading to decreased levels of translation initiation. However, expression of ATF4 or CHOP was not induced by UVB as compared with traditional ISR activators. The rationale for this discordant response is that ATF4 mRNA is reduced by UVB, and despite its ability to be preferentially translated, there are diminished levels of available transcript. Forced expression of ATF4 and CHOP protein before UVB irradiation significantly enhanced apoptosis, suggesting that this portion of the ISR is deleterious in keratinocytes following UVB. Inhibition of eIF2-P and translational control reduced viability following UVB that was alleviated by cycloheximide (CHX), indicating that translation repression through eIF2-P is central to keratinocyte survival.
机译:这项研究描述了UVB调节人角质形成细胞中蛋白质合成的机制,以及翻译控制在细胞存活中的重要性。翻译起始受真核起始因子2(eIF2-P)磷酸化的调节,该磷酸化导致整体蛋白质合成减少,同时与选定的应激相关转录本(如激活转录因子4(ATF4))的翻译增强有关。 ATF4是整合应激反应(ISR)的转录激活因子,它具有细胞保护功能以及通过下游转录调节因子C / EBP同源蛋白(CHOP; GADD153 / DDIT3)的凋亡信号。我们确定UVB辐射是角质形成细胞中eIF2-P的有效诱导剂,导致翻译起始水平降低。但是,与传统的ISR激活剂相比,UVB不会诱导ATF4或CHOP的表达。这种不一致反应的基本原理是UVB会降低ATF4 mRNA的表达,尽管它具有优先翻译的能力,但可用转录物的水平却有所降低。 UVB照射前ATF4和CHOP蛋白的强制表达显着增强了细胞凋亡,这表明ISB的这一部分在UVB后对角质形成细胞有害。 eIF2-P的抑制和翻译控制降低了UVB后被环己酰亚胺(CHX)缓解的活力,这表明通过eIF2-P进行的翻译抑制对角质形成细胞的生存至关重要。

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