Golgi stress mediates redox imbalance and ferroptosis in human cells
Golgi stress mediates redox imbalance and ferroptosis in human cells
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DOI：
10.1038/s42003-018-0212-6
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发表时间：
2018-01-01
影响因子：
5.9
通讯作者：
Reiling, Jan H.
中科院分区：
文献类型：
--
作者：
Alborzinia, Named;Ignashkova, Tatiana I.;Reiling, Jan H.
包括AMF-26/M-COPA、布雷菲德菌素A和杀高尔基体剂A在内的几种高尔基体分散化合物的细胞毒性活性先前已显示诱导自噬或凋亡。在这里，我们证明，这些高尔基体干扰物也触发铁凋亡，一种非凋亡形式的细胞死亡，其特征在于铁依赖性脂质氧化降解。铁凋亡的抑制剂不仅对抗细胞死亡，而且它们还保护免受高尔基体分散和响应于几种高尔基体应激剂的蛋白质分泌抑制。此外，应用亚致死剂量的铁凋亡诱导剂如erastin和索拉非尼、低胱氨酸生长条件或SLC 7A 11和GPX 4的遗传敲低都类似地保护细胞免受高尔基体应激并导致ACSL 4、SLC 7A 5、SLC 7A 11或GPX 4水平的调节。总的来说，这项研究表明了一个以前未被认识到的功能高尔基体，其中涉及细胞氧化还原控制和防止铁凋亡细胞死亡。
Cytotoxic activities of several Golgi-dispersing compounds including AMF-26/M-COPA, brefeldin A and golgicide A have previously been shown to induce autophagy or apoptosis. Here, we demonstrate that these Golgi disruptors also trigger ferroptosis, a non-apoptotic form of cell death characterized by iron-dependent oxidative degradation of lipids. Inhibitors of ferroptosis not only counteract cell death, but they also protect from Golgi dispersal and inhibition of protein secretion in response to several Golgi stress agents. Furthermore, the application of sublethal doses of ferroptosis-inducers such as erastin and sorafenib, low cystine growth conditions, or genetic knockdown of SLC7A11 and GPX4 all similarly protect cells from Golgi stress and lead to modulation of ACSL4, SLC7A5, SLC7A11 or GPX4 levels. Collectively, this study suggests a previously unrecognized function of the Golgi apparatus, which involves cellular redox control and prevents ferroptotic cell death.