Protein phosphatase 2A stimulates activation of TFEB and TFE3 transcription factors in response to oxidative stress
Protein phosphatase 2A stimulates activation of TFEB and TFE3 transcription factors in response to oxidative stress
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DOI：
10.1074/jbc.ra118.003471
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发表时间：
2018-08-10
影响因子：
4.8
通讯作者：
Puertollano, Rosa
中科院分区：
文献类型：
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作者：
Martina, Jose A.;Puertollano, Rosa
对应激条件的适应和反应是所有细胞必须完成以维持或恢复细胞稳态的基本过程。细胞有大量的反应途径来减轻不同环境压力的影响。转录调节因子转录因子EB（TFEB）和与IGHM增强子3结合的转录因子（TFE3）在这些应激途径的控制中起关键作用。因此，了解它们在不同胁迫条件下的调节具有重要意义。在这里，使用一系列的人类和小鼠细胞，我们表明，TFEB和TFE3被激活后，诱导急性氧化应激亚砷酸通过mTOR复合物1（mTORC 1）的独立过程。我们发现，亚砷酸盐刺激的TFEB和TFE3激活的机制，而不是涉及蛋白磷酸酶2A（PP2A）介导的去磷酸化在Ser-211和Ser-321，分别。消耗PP2A的催化（PPP2CA + B）或调节（PPP2R2A/B55）亚基，以及用特异性抑制剂冈田酸使PP2A失活，消除了亚砷酸钠对TFE B和TFE 3的激活。相反，神经酰胺或鞘氨醇样化合物FTY 720激活PP2A足以诱导TFE3核转位。MS分析显示，PP2A在几个残基处使TFEB去磷酸化，包括Ser-109、Ser-114、Ser-122和Ser-211，从而促进TFEB活化。总的来说，这项工作确定了一个关键机制，激活TFEB和TFE3，而不关闭mTORC 1活动。我们认为，这种机制可能使一些细胞类型，如免疫细胞或癌细胞，需要同时TFEB/TFE3和mTORC 1信号传导，以生存和实现强大的细胞生长在压力环境中。
Adaptations and responses to stress conditions are fundamental processes that all cells must accomplish to maintain or restore cellular homeostasis. Cells have a plethora of response pathways to mitigate the effect of different environmental stressors. The transcriptional regulators transcription factor EB (TFEB) and transcription factor binding to IGHM enhancer 3 (TFE3) play a key role in the control of these stress pathways. Therefore, understanding their regulation under different stress conditions is of great interest. Here, using a range of human and murine cells, we show that TFEB and TFE3 are activated upon induction of acute oxidative stress by sodium arsenite via an mTOR complex 1 (mTORC1)-independent process. We found that the mechanism of arsenite-stimulated TFEB and TFE3 activation instead involves protein phosphatase 2A (PP2A)-mediated dephosphorylation at Ser-211 and Ser-321, respectively. Depletion of either the catalytic (PPP2CA+B) or regulatory (PPP2R2A/B55) subunits of PP2A, as well as PP2A inactivation with the specific inhibitor okadaic acid, abolished TFEB and TFE3 activation in response to sodium arsenite. Conversely, PP2A activation by ceramide or the sphingosine-like compound FTY720 was sufficient to induce TFE3 nuclear translocation. MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation. Overall, this work identifies a critical mechanism that activates TFEB and TFE3 without turning off mTORC1 activity. We propose that this mechanism may enable some cell types such as immune or cancer cells that require simultaneous TFEB/TFE3 and mTORC1 signaling to survive and achieve robust cell growth in stressful environments.