Kinome screen of ferroptosis reveals a novel role of ATM in regulating iron metabolism
Kinome screen of ferroptosis reveals a novel role of ATM in regulating iron metabolism
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DOI：
10.1038/s41418-019-0393-7
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发表时间：
2020-03-01
影响因子：
12.4
通讯作者：
Chi, Jen-Tsan
中科院分区：
文献类型：
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作者：
Chen, Po-Han;Wu, Jianli;Chi, Jen-Tsan
铁下垂是一种特殊的铁依赖细胞死亡，与致命的脂质过氧化有关。铁下垂的调节可能具有治疗潜力，因为它与多种人类疾病有关，并具有潜在的抗肿瘤活性。然而，关于铁性上睑下垂的潜在机制和遗传决定因素，仍有许多未知之处。鉴于激酶在大多数生物过程中的关键作用，以及各种激酶抑制剂的可用性，我们试图系统地确定对铁性上睑下垂至关重要的激酶。我们在MDA-MB-231细胞中进行了一项基于遗传的正向动态组筛查，以对抗由半胱氨酸剥夺引发的铁下垂。这一筛选确定了34个参与TNFa和NF-kB信号转导的重要激酶。出乎意料的是，DNA损伤反应丝氨酸/苏氨酸激酶ATM(在共济失调-毛细血管扩张症中突变)被发现是铁性下垂的关键。ATM的药理或遗传抑制持续地将多个癌细胞从由半胱氨酸剥夺或擦除蛋白引发的铁下垂中解救出来。与经典的DNA损伤途径不同，ATM抑制通过增加与铁储存(铁蛋白重链和轻链，FTH1和FTL)和出口(铁蛋白，FPN1)有关的铁调节因子的表达来拯救铁下垂。在ATM抑制过程中，这些铁调节因子的协同变化导致活性铁的降低，从而防止铁依赖性下垂。此外，我们发现ATM抑制增强了金属调节转录因子1(MTF1)的核转位，负责调节铁蛋白/FPN1的表达和铁下垂保护。MTF-1的基因缺失取消了ATM对铁调节元件的调节，并使细胞对铁下垂重新敏感。总之，我们已经确定了一个意想不到的ATM-MTF1-铁蛋白/FPN1调节轴作为铁下垂的新决定因素，通过调节不稳定的铁水平。
Ferroptosis is a specialized iron- dependent cell death that is associated with lethal lipid peroxidation. Modulation of ferroptosis may have therapeutic potential since it has been implicated in various human diseases as well as potential antitumor activities. However, much remains unknown about the underlying mechanisms and genetic determinants of ferroptosis. Given the critical role of kinases in most biological processes and the availability of various kinase inhibitors, we sought to systemically identify kinases essential for ferroptosis. We performed a forward genetic-based kinome screen against ferroptosis in MDA-MB-231 cells triggered by cystine deprivation. This screen identified 34 essential kinases involved in TNFa and NF-kB signaling. Unexpectedly, the DNA damage response serine/threonine kinase ATM (mutated in Ataxia- Telangiectasia) was found to be essential for ferroptosis. The pharmacological or genetic inhibition of ATM consistently rescued multiple cancer cells from ferroptosis triggered by cystine deprivation or erastin. Instead of the canonical DNA damage pathways, ATM inhibition rescued ferroptosis by increasing the expression of iron regulators involved in iron storage (ferritin heavy and light chain, FTH1 and FTL) and export (ferroportin, FPN1). The coordinated changes of these iron regulators during ATM inhibition resulted in a lowering of labile iron and prevented the irondependent ferroptosis. Furthermore, we found that ATM inhibition enhanced the nuclear translocation of metal-regulatory transcription factor 1 (MTF1), responsible for regulating expression of Ferritin/FPN1 and ferroptosis protection. Genetic depletion of MTF-1 abolished the regulation of iron-regulatory elements by ATM and resensitized the cells to ferroptosis. Together, we have identified an unexpected ATM-MTF1-Ferritin/FPN1 regulatory axis as novel determinants of ferroptosis through regulating labile iron levels.