Phospholipase iPLA(2)β averts ferroptosis by eliminating a redox lipid death signal.
Phospholipase iPLA(2)β averts ferroptosis by eliminating a redox lipid death signal.
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磷脂酶 iPLA2β 通过消除氧化还原脂质死亡信号来避免铁死亡
DOI：
10.1038/s41589-020-00734-x
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发表时间：
2021-04
影响因子：
14.8
通讯作者：
Kagan VE
中科院分区：
文献类型：
--
作者：
Sun WY;Tyurin VA;Mikulska-Ruminska K;Shrivastava IH;Anthonymuthu TS;Zhai YJ;Pan MH;Gong HB;Lu DH;Sun J;Duan WJ;Korolev S;Abramov AY;Angelova PR;Miller I;Beharier O;Mao GW;Dar HH;Kapralov AA;Amoscato AA;Hastings TG;Greenamyre TJ;Chu CT;Sadovsky Y;Bahar I;Bayır H;Tyurina YY;He RR;Kagan VE
铁、硫醇和脂质失配引发的铁下沉导致15-羟基过氧(Hp)-花生四烯酰基-磷脂酰乙醇胺（15-HpETE-PE）的积累，该物质由15-脂氧合酶（15-LOX）和支架蛋白磷脂酰乙醇胺（PE）结合蛋白（PEBP）1的复合物生成。由于Ca2+非依赖性磷脂酶A2β （iPLA2β， pla2g6或pnpla9基因）可以优先水解过氧化磷脂，它可能消除铁致15-HpETE-PE死亡信号。在这里，我们证明通过水解15-HpETE-PE， iPLA2β可以避免铁下垂，而其遗传或药物失活则使细胞对铁下垂敏感。考虑到pla2g6突变与神经退行性变有关，我们检查了帕金森病（PD）相关突变（fPDR747W）患者的成纤维细胞，发现选择性地降低了15-HpETE-PE水解活性，15-HpETE-PE积累和对铁下垂的敏感性升高。crispr - cas9工程的pnpla9r748w /R748Wmice表现出进行性帕金森运动缺陷和15-HpETE-PE积累。在鱼tenone输注的帕金森大鼠和α-突触核蛋白突变体sncaa53t小鼠中脑中也检测到15-HpETE-PE水平升高，iPLA2β表达降低，出现pd相关表型。因此，iPLA2β是一种新的铁下垂调节因子，其突变可能与PD的发病机制有关。
Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca2+-independent phospholipase A2β (iPLA2β,PLA2G6orPNPLA9gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2β averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given thatPLA2G6mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson’s disease (PD)-associated mutation (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineeredPnpla9R748W/R748Wmice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutantSncaA53Tmice, with decreased iPLA2β expression and a PD-relevant phenotype. Thus, iPLA2β is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.
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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
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
DOI：
10.1073/pnas.2009201117
发表时间：
2020-11-03
影响因子：
11.1
作者：
Beharier, Ofer;Tyurin, Vladimir A.;Sadovsky, Yoel
通讯作者：
Sadovsky, Yoel
影响因子：
8.6
作者：
Kauther, Kai Michael;Hoeft, Christine;Moeller, Jens Carsten
通讯作者：
Moeller, Jens Carsten