iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4.
iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4.
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DOI：
10.1038/s41467-021-23902-6
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发表时间：
2021-06-15
影响因子：
16.6
通讯作者：
Gu W
中科院分区：
文献类型：
--
作者：
Chen D;Chu B;Yang X;Liu Z;Jin Y;Kon N;Rabadan R;Jiang X;Stockwell BR;Gu W
在这里，我们确定iPLA2β是P53引起的铁下垂的关键调节因子，在ROS诱导的应激反应中。已知的钙非依赖性磷脂酶iPLA2β可以从脂类的甘油骨架上裂解酰基尾巴，并从磷脂中释放氧化脂肪酸。我们发现，iPLA2β介导的过氧化脂质解毒足以抑制ROS诱导的应激条件下P53驱动的铁下垂，即使在Gpx4缺失的细胞中也是如此。此外，iPLA2β在人类癌症中过表达；抑制内源性iPLA2β使肿瘤细胞对P53驱动的铁性下垂敏感，并在异种移植小鼠模型中促进P53依赖的肿瘤抑制。这些结果表明，iPLA2β以不依赖于Gpx4的方式作为主要的铁下垂抑制因子。值得注意的是，与Gpx4不同，iPLA2β的缺失对正常组织的正常发育或细胞活力没有明显影响，但iPLA2β在调节ROS诱导的应激引起的铁下垂方面起着重要作用。因此，我们的研究表明，iPLA2β是一种有希望的治疗靶点，用于激活铁下垂介导的肿瘤抑制，而不存在严重的毒性问题。P53能够诱导铁性下垂，以应对ROS诱导的应激反应，并抑制肿瘤生长。在这里，作者表明，iPLA2β通过裂解和解毒过氧化脂质来抑制P53介导的铁下垂，这不依赖于典型的铁下垂调节剂Gpx4。
Here, we identify iPLA2β as a critical regulator for p53-driven ferroptosis upon reactive oxygen species (ROS)-induced stress. The calcium-independent phospholipase iPLA2β is known to cleave acyl tails from the glycerol backbone of lipids and release oxidized fatty acids from phospholipids. We found that iPLA2β-mediated detoxification of peroxidized lipids is sufficient to suppress p53-driven ferroptosis upon ROS-induced stress, even in GPX4-null cells. Moreover, iPLA2β is overexpressed in human cancers; inhibition of endogenous iPLA2β sensitizes tumor cells to p53-driven ferroptosis and promotes p53-dependent tumor suppression in xenograft mouse models. These results demonstrate that iPLA2β acts as a major ferroptosis repressor in a GPX4-independent manner. Notably, unlike GPX4, loss of iPLA2β has no obvious effect on normal development or cell viability in normal tissues but iPLA2β plays an essential role in regulating ferroptosis upon ROS-induced stress. Thus, our study suggests that iPLA2β is a promising therapeutic target for activating ferroptosis-mediated tumor suppression without serious toxicity concerns. p53 is able to induce ferroptosis in response to reactive oxygen species (ROS)-induced stress and suppresses tumour growth. Here, the authors show that iPLA2β suppresses p53-medated ferroptosis by cleaving and detoxifying peroxidized lipids and that this is independent of canonical ferroptosis regulator GPX4.
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ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
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
通讯作者：
Conrad M
影响因子：
14.8
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
通讯作者：
Bayır H
DOI：
10.1146/annurev-pathol-012414-040349
发表时间：
2016-05-23
期刊：
Annual review of pathology
影响因子：
--
作者：
Karni-Schmidt O;Lokshin M;Prives C
通讯作者：
Prives C
影响因子：
10.5
作者：
Jennis M;Kung CP;Basu S;Budina-Kolomets A;Leu JI;Khaku S;Scott JP;Cai KQ;Campbell MR;Porter DK;Wang X;Bell DA;Li X;Garlick DS;Liu Q;Hollstein M;George DL;Murphy ME
通讯作者：
Murphy ME
影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M