CFTR supports cell death through ROS-dependent activation of TMEM16F (anoctamin 6)
CFTR supports cell death through ROS-dependent activation of TMEM16F (anoctamin 6)
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DOI：
10.1007/s00424-017-2065-0
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发表时间：
2017-09
期刊：
影响因子：
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通讯作者：
Filipa Simões;J. Ousingsawat;Podchanart Wanitchakool;Ana Fonseca;Inês Cabrita;R. Benedetto;R. Schreiber;K. Kunzelmann
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文献类型：
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作者：
Filipa Simões;J. Ousingsawat;Podchanart Wanitchakool;Ana Fonseca;Inês Cabrita;R. Benedetto;R. Schreiber;K. Kunzelmann
囊性纤维化跨膜传导调节因子（CFTR）是上皮细胞顶膜上重要的氯离子和碳酸氢根通道。CFTR也在早期提出将谷胱甘肽（GSH）从气道上皮细胞中导出，以富集在顶端气道表面液体中，以中和活性氧（ROS）。虽然早期的研究表明，释放GSH的野生型（wt）CFTR可能会导致细胞溶质ROS的增加，我们没有检测到不同的ROS水平在细胞表达的野生型CFTR和突变型F508 del-CFTR，独立于CFTR激活或暴露于ROS供体叔丁基氢过氧化物。Ca 2+激活的磷脂乱序酶和离子通道TMEM 16 F（anoctamin 6，ANO 6）也在气道细胞中表达。ANO 6产生外向整流Cl−电流（ORCC）和乱序质膜磷脂时，激活增加细胞溶质ROS和连续的质膜脂质过氧化。CFTR可能通过将信号蛋白易位至质膜来增强ANO 6活性。目前的数据表明，CFTR表达细胞中增强的细胞死亡是由于ANO 6活性的上调。在ANO 6基因敲除小鼠中，肠上皮中凋亡细胞的数量大幅减少，支持ANO 6对细胞死亡的作用。因此，ANO 6和CFTR协同作用于ROS介导的细胞死亡，其不被cAMP依赖性刺激进一步增强。我们提出，ANO 6支持与CFTR表达相关的细胞死亡，可能是通过诱导铁凋亡。
Cystic fibrosis transmembrane conductance regulator (CFTR) is the essential chloride and bicarbonate channel in the apical membrane of epithelial cells. CFTR was also proposed earlier to conduct glutathione (GSH) out of airway epithelial cells to be enriched in the apical airway surface liquid to neutralize reactive oxygen species (ROS). Although earlier studies suggested that release of GSH by wild type (wt) CFTR may lead to an increase in cytosolic ROS, we did not detect different ROS levels in cells expressing wt-CFTR and mutant F508del-CFTR, independent of CFTR-activation or exposure to the ROS donor tert-butyl hydroperoxide. The Ca2+-activated phospholipid scramblase and ion channel TMEM16F (anoctamin 6, ANO6) is also expressed in airway cells. ANO6 produced outwardly rectifying Cl−currents (ORCC) and scrambled plasma membrane phospholipids when activated by increase in cytosolic ROS and consecutive peroxidation of plasma membrane lipids. ANO6 activity is enhanced by CFTR, probably through translocation of signaling proteins to the plasma membrane. The present data suggest that enhanced cell death in CFTR-expressing cells is due to upregulation of ANO6-activity. In ANO6 knockout mice, the number of apoptotic cells in the intestinal epithelium was strongly reduced, supporting the role of ANO6 for cell death. Thus, ANO6 and CFTR act cooperatively on ROS-mediated cell death, which is not further augmented by cAMP-dependent stimulation. We propose that ANO6 supports cell death correlated with expression of CFTR, possibly by inducing ferroptosis.