From the Laboratory of Environmental Molecular Physiology.
J Biol Chem. 2014 Feb 14;289(7):3888-900. doi: 10.1074/jbc.M113.491217. Epub 2013 Dec 30.
Activating transcription factor 5 (ATF5) is a stress-response transcription factor that responds to amino acid limitation and exposure to cadmium chloride (CdCl2) and sodium arsenite (NaAsO2). The N-terminal amino acids contribute to the destabilization of the ATF5 protein in steady-state conditions and serve as a stabilization domain in the stress response after CdCl2 or NaAsO2 exposure. In this study, we show that interleukin 1β (IL-1β), a proinflammatory cytokine, increases the expression of ATF5 protein in HepG2 hepatoma cells in part by stabilizing the ATF5 protein. The N-terminal domain rich in hydrophobic amino acids that is predicted to form a hydrophobic network was responsible for destabilization in steady-state conditions and served as an IL-1β response domain. Furthermore, IL-1β increased the translational efficiency of ATF5 mRNA via the 5' UTRα and phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α). ATF5 knockdown in HepG2 cells up-regulated the IL-1β-induced expression of the serum amyloid A 1 (SAA1) and SAA2 genes. Our results show that the N-terminal hydrophobic amino acids play an important role in the regulation of ATF5 protein expression in IL-1β-mediated immune response and that ATF5 is a negative regulator for IL-1β-induced expression of SAA1 and SAA2 in HepG2 cells.
激活转录因子 5（ATF5）是一种应激反应转录因子，对氨基酸限制以及暴露于氯化镉（CdCl2）和亚砷酸钠（NaAsO2）有响应。N 端氨基酸有助于在稳态条件下使 ATF5 蛋白不稳定，并在暴露于 CdCl2 或 NaAsO2 后作为应激反应的稳定域。在这项研究中，我们表明白细胞介素 1β（IL-1β），一种促炎细胞因子，通过稳定 ATF5 蛋白，部分增加 HepG2 肝癌细胞中 ATF5 蛋白的表达。富含疏水性氨基酸的 N 端结构域，预测形成疏水性网络，在稳态条件下负责不稳定，并作为 IL-1β 反应域。此外，IL-1β 通过 5'UTRα 和真核翻译起始因子 2α（eIF2α）的磷酸化增加 ATF5 mRNA 的翻译效率。在 HepG2 细胞中敲低 ATF5 会上调 IL-1β 诱导的血清淀粉样蛋白 A1（SAA1）和 SAA2 基因的表达。我们的结果表明，N 端疏水性氨基酸在 IL-1β 介导的免疫反应中调节 ATF5 蛋白表达中起重要作用，并且 ATF5 是 HepG2 细胞中 IL-1β 诱导的 SAA1 和 SAA2 表达的负调节剂。
