NOXA upregulation by the prohibitin‐binding compound fluorizoline is transcriptionally regulated by integrated stress response‐induced ATF3 and ATF4,The FEBS Journal

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NOXA upregulation by the prohibitin‐binding compound fluorizoline is transcriptionally regulated by integrated stress response‐induced ATF3 and ATF4
The FEBS Journal ( IF 5.5 ) Pub Date : 2020-07-10 , DOI: 10.1111/febs.15480
Sonia Núñez-Vázquez ₁ , Ismael Sánchez-Vera ₁ , José Saura-Esteller ₁ , Ana M Cosialls ₁ , Anaïs F M Noisier ₂ , Fernando Albericio ₃ , Rodolfo Lavilla ₂ , Gabriel Pons ₁ , Daniel Iglesias-Serret _{1,

4} , Joan Gil ₁

Affiliation

Fluorizoline is a new synthetic molecule that induces p53‐independent apoptosis, in several tumor cell lines and in primary leukemia cells, by selectively targeting prohibitins (PHBs). In this study, we describe how fluorizoline induces BCL‐2 homology 3‐only protein NOXA, without modulating the protein levels of anti‐apoptotic B‐cell lymphoma‐2 (BCL‐2) family members prior to caspase activation, as well as how it synergizes with the BCL‐2 and BCL‐X_L inhibitor ABT‐737 to induce apoptosis. Interestingly, fluorizolinetreatment triggers the activation of the integrated stress response (ISR) in HeLa and HAP1 cells, with increased eukaryotic translation initiation factor 2α phosphorylation, and induction of ATF3, ATF4, and CHOP. Moreover, PHB downregulation induces similar ISR activation and apoptosis as with fluorizoline treatment. In addition, we studied the essential role of the pro‐apoptotic protein NOXA in fluorizoline‐induced apoptosis and we describe its mechanism of induction in HeLa and HAP1 cells. Moreover, we identified ATF3 and ATF4 as the transcription factors that bind to NOXA promoter upon fluorizoline treatment. Furthermore, using ATF3 and ATF4 CRISPR HeLa and HAP1 cells, we confirmed that both factors mediate the induction of NOXA and apoptosis by fluorizoline. In conclusion, fluorizoline treatment triggers the activation of the ISR that results in the induction of ATF3 and ATF4, important regulators of NOXA transcription in fluorizoline‐induced apoptosis.

中文翻译：

禁忌素结合化合物氟唑啉对NOXA的上调受应激反应诱导的ATF3和ATF4的转录调控

氟唑啉是一种新的合成分子，它通过选择性地靶向抑制素（PHB），在几种肿瘤细胞系和原发性白血病细胞中诱导不依赖p53的细胞凋亡。在这项研究中，我们描述了氟唑啉如何诱导BCL-2同源性3蛋白NOXA，而不在胱天蛋白酶激活之前调节抗凋亡B细胞淋巴瘤2（BCL-2）家族成员的蛋白水平，以及如何它与BCL-2和BCL-X _L协同工作抑制剂ABT-737诱导细胞凋亡。有趣的是，氟唑啉处理触发了HeLa和HAP1细胞中的整合应激反应（ISR）的激活，并伴随着真核翻译起始因子2α磷酸化的增强，以及ATF3，ATF4和CHOP的诱导。此外，PHB的下调诱导了与氟唑啉处理类似的ISR活化和凋亡。此外，我们研究了促凋亡蛋白NOXA在氟唑啉诱导的细胞凋亡中的重要作用，并描述了其在HeLa和HAP1细胞中的诱导机制。此外，我们确定ATF3和ATF4为在氟唑啉处理后与NOXA启动子结合的转录因子。此外，使用ATF3和ATF4在CRISPR HeLa和HAP1细胞中，我们证实了这两个因素均通过氟唑啉介导NOXA的诱导和细胞凋亡。总之，氟唑啉治疗触发了ISR的激活，从而导致了ATF3和ATF4的诱导，ATF3和ATF4是氟唑啉诱导的细胞凋亡中NOXA转录的重要调节剂。

更新日期：2020-07-10

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