小柯机器人

FSP1蛋白抑制细胞铁死亡
2019-10-22 14:34

美国加州大学伯克利分校James A. Olzmann研究组研究发现,辅酶Q氧化还原酶FSP1以与GPX4蛋白平行的方式参与抑制细胞铁死亡。相关论文2019年10月21日在线发表于《自然》杂志。

使用合成致死性CRISPR–Cas9筛选,研究人员鉴定出铁死亡抑制蛋白1(FSP1,以前称为线粒体凋亡诱导因子2,AIFM2)是一种有效的铁死亡抗性因子。数据表明,肉豆蔻酰化将FSP1募集到质膜,在其中它作为氧化还原酶起作用,从而降低辅酶Q10(CoQ),生成亲脂性自由基捕获抗氧化剂(RTA),从而阻止脂质过氧化物的传播。研究人员进一步发现,FSP1表达与数百种癌细胞系中的铁死亡耐药性正相关,并且FSP1介导培养的肺癌细胞和小鼠肿瘤异种移植物中对铁死亡的耐药性。因此,这些数据确定FSP1是非线粒体CoQ抗氧化剂系统的关键成分,该系统与基于谷胱甘肽的经典GPX4途径平行起作用。这些发现定义了一条新的抑制铁锈病的途径,并表明FSP1的药理抑制作用可能提供一种有效的策略,可以使癌细胞对铁死亡诱导的化学疗法敏感。

据介绍,铁死亡是一种受调节的细胞死亡形式,它是由铁依赖的脂质过氧化作用所引起。谷胱甘肽依赖性脂质氢过氧化物酶——谷胱甘肽过氧化物酶4(GPX4),通过将脂质氢过氧化物转化为无毒脂质醇来预防肥大病。铁死亡与细胞死亡有关,该细胞死亡是几种退化性疾病的基础,通过抑制GPX4诱导铁死亡可作为触发癌细胞死亡的治疗策略。但是,在癌细胞系中对GPX4抑制剂的敏感性差异很大,这表明其他因素决定了对铁死亡的抗性。

附:英文原文
 
Title:The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis
 
Author:Kirill Bersuker, Joseph Hendricks, Zhipeng Li, Leslie Magtanong, Breanna Ford, Peter H. Tang, Melissa A. Roberts, Bingqi Tong, Thomas J. Maimone, Roberto Zoncu, Michael C. Bassik, Daniel K. Nomura, Scott J. Dixon & James A. Olzmann 
 
Issue&Volume:21 October 2019
 
Abstract: 
 
Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols3,4. Ferroptosis has been implicated in the cell death that underlies several degenerative conditions2, and induction of ferroptosis by inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death5. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines6, suggesting that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR–Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q10 (CoQ), generating a lipophilic radical-trapping antioxidant (RTA) that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumor xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a new ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutics.
 
DOI:10.1038/s41586-019-1705-2
 
Source: https://www.nature.com/articles/s41586-019-1705-2

 

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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