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Activating Transcription Factor 4 Is Translationally Regulated by Hypoxic Stress

机译：激活转录因子4受缺氧应激的翻译调节。

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Hypoxic stress results in a rapid and sustained inhibition of protein synthesis that is at least partially mediated by eukaryotic initiation factor 2α (eIF2α) phosphorylation by the endoplasmic reticulum (ER) kinase PERK. Here we show through microarray analysis of polysome-bound RNA in aerobic and hypoxic HeLa cells that a subset of transcripts are preferentially translated during hypoxia, including activating transcription factor 4 (ATF4), an important mediator of the unfolded protein response. Changes in mRNA translation during the unfolded protein response are mediated by PERK phosphorylation of the translation initiation factor eIF2α at Ser-51. Similarly, PERK is activated and is responsible for translational regulation under hypoxic conditions, while inducing the translation of ATF4. The overexpression of a C-terminal fragment of GADD34 that constitutively dephosphorylates eIF2α was able to attenuate the phosphorylation of eIF2α and severely inhibit the induction of ATF4 in response to hypoxic stress. These studies demonstrate the essential role of ATF4 in the response to hypoxic stress, define the pathway for its induction, and reveal that GADD34, a target of ATF4 activation, negatively regulates the eIF2α-mediated inhibition of translation. Taken with the concomitant induction of additional ER-resident proteins identified by our microarray analysis, this study suggests an important integrated response between ER signaling and the cellular adaptation to hypoxic stress.
机译：低氧胁迫导致蛋白质合成的快速持续抑制，该抑制至少部分由内质网（ER）激酶PERK的真核起始因子2α（eIF2α）磷酸化介导。在这里，我们通过对有氧和低氧HeLa细胞中结合多核糖体的RNA进行的微阵列分析显示，缺氧时转录子的一部分优先被翻译，包括激活转录因子4（ATF4），这是未折叠蛋白应答的重要介体。在未折叠的蛋白质反应过程中，mRNA翻译的变化是由翻译起始因子eIF2α在Ser-51的PERK磷酸化介导的。同样，PERK被激活，并在缺氧条件下负责翻译调控，同时诱导ATF4的翻译。组成性地使eIF2α去磷酸化的GADD34的C端片段的过表达能够减弱eIF2α的磷酸化并严重抑制ATF4对低氧应激的诱导。这些研究证明了ATF4在低氧应激反应中的重要作用，定义了其诱导途径，并揭示了ADD4活化的靶点GADD34负调控eIF2α介导的翻译抑制。伴随我们的微阵列分析鉴定出的其他内质网驻留蛋白的诱导，这项研究表明内质网信号传导和细胞对低氧应激的适应性之间的重要综合反应。

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