ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.
ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.
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ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
DOI：
10.1038/nchembio.2239
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发表时间：
2017-01
影响因子：
14.8
通讯作者：
Conrad M
中科院分区：
文献类型：
--
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
铁下垂是一种由谷胱甘肽过氧化物酶4(Gpx4)控制的调节性坏死性细胞死亡。目前，需要能够预测敏感性和/或耐药性的机制，以及可能被用来调节这种形式的细胞死亡的机制。我们应用了两种独立的方法，基于全基因组CRISPR的遗传筛查和耐铁下垂细胞系的微阵列分析，以发现酰辅酶A合成酶长链家族成员4(Acsl4)是执行铁下垂的必要成分。具体地说，Gpx4/Acsl4双基因敲除细胞对铁下垂表现出前所未有的抵抗力。从机理上讲，Acsl4使细胞膜富含长的多不饱和ω6脂肪酸。此外，Acsl4在一组基底细胞样乳腺癌细胞系中优先表达，并预测它们对铁下垂的敏感性。我们进一步证明，在抗糖尿病化合物类化合物噻唑烷二酮类中，Acsl4的药理靶向改善了铁下垂小鼠模型的组织死亡，表明抑制Acsl4是预防铁下垂相关疾病的一种可行的治疗方法。
Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate this form of cell death are needed. We applied two independent approaches, a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines to uncover acyl-CoA synthetase long-chain family member 4 (Acsl4) as an essential component for ferroptosis execution. Specifically, Gpx4/Acsl4 double knockout cells presented an unprecedented resistance to ferroptosis. Mechanistically, Acsl4 enriches cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, Acsl4 is preferentially expressed in a panel of basal-like breast cancer cell lines and predicts their sensitivity to ferroptosis. We further demonstrate that pharmacological targeting of Acsl4 with the antidiabetic compound class, thiazolidinediones, ameliorates tissue demise in a murine model of ferroptosis, suggesting that Acsl4 inhibition is a viable therapeutic approach to prevent ferroptosis-related diseases.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
4
作者：
Dixon SJ;Winter GE;Musavi LS;Lee ED;Snijder B;Rebsamen M;Superti-Furga G;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
--
作者：
Orlando UD;Castillo AF;Dattilo MA;Solano AR;Maloberti PM;Podesta EJ
通讯作者：
Podesta EJ
影响因子：
29.4
作者：
Aithal, Guruprasad P.;Thomas, James A.;Weeber, Jonathan
通讯作者：
Weeber, Jonathan
影响因子：
13.5
作者：
Kuboki, Satoshi;Shin, Thomas;Lentsch, Alex B.
通讯作者：
Lentsch, Alex B.