Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis.
Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis.
复制标题
DOI：
10.1038/nchembio.2079
复制
发表时间：
2016-07
影响因子：
14.8
通讯作者：
Stockwell BR
中科院分区：
文献类型：
--
作者：
Shimada K;Skouta R;Kaplan A;Yang WS;Hayano M;Dixon SJ;Brown LM;Valenzuela CA;Wolpaw AJ;Stockwell BR
细胞凋亡被称为程序性细胞死亡。一些非凋亡性细胞死亡越来越多地被认为是受基因控制的，或者说是“受控制的”。然而，这些可供选择的细胞死亡机制的全部范围和多样性仍然未知。在这里，我们调查了药物可获得的细胞死亡机制的概况。在56种不依赖于caspase的致死化合物中，调制图谱显示其中10种诱导了三种类型的受调控的非凋亡性细胞死亡。对十种药物中的一种进行了先导优化，发现了FIN56，一种铁性下垂的特异性诱导剂。当脂质修复酶Gpx4被抑制时，就会发生铁下垂。我们发现FIN56促进了Gpx4的降解。我们进行了化学蛋白质组学研究，发现FIN56还以一种独立于Gpx4降解的方式与角鲨烯合成酶结合并激活角鲨烯合成酶，角鲨烯合成酶参与胆固醇合成。这些发现表明，脂类代谢紊乱与铁性下垂有关。这种系统的方法是发现和表征新的细胞死亡表型的一种手段。
Apoptosis is known as programmed cell death. Some non-apoptotic cell death is increasingly recognized as genetically controlled, or ‘regulated’. However, the full extent and diversity of these alternative cell death mechanisms remains uncharted. Here, we surveyed the landscape of pharmacologically-accessible cell death mechanisms. Of 56 caspase-independent lethal compounds, modulatory profiling revealed ten inducing three types of regulated non-apoptotic cell death. Lead optimization of one of the ten resulted in the discovery of FIN56, a specific inducer of ferroptosis. Ferroptosis occurs when the lipid repair enzyme GPX4 is inhibited. We found that FIN56 promotes degradation of GPX4. We performed chemoproteomics to reveal that FIN56 also binds to and activates squalene synthase, an enzyme involved in the cholesterol synthesis, in a manner independent of GPX4 degradation. These discoveries reveal that dysregulation of lipid metabolism is associated with ferroptosis. This systematic approach is a means to discover and characterize novel cell death phenotypes.