磷脂酶 iPLA2β 通过消除氧化还原脂质死亡信号来避免铁死亡
Nature Chemical Biology
(
IF12.9
)
Pub Date : 2021-02-04, DOI: 10.1038/s41589-020-00734-x
Wan-Yang Sun
1,
2,
3
,
Vladimir A Tyurin
1
,
Karolina Mikulska-Ruminska
4,
5
,
Indira H Shrivastava
1,
5
,
Tamil S Anthonymuthu
1,
6
,
Yu-Jia Zhai
2,
3
,
Ming-Hai Pan
2,
3
,
Hai-Biao Gong
2,
3
,
Dan-Hua Lu
2,
3
,
Jie Sun
2,
3
,
Wen-Jun Duan
2,
3
,
Sergey Korolev
7
,
Andrey Y Abramov
8
,
Plamena R Angelova
8
,
Ian Miller
7
,
Ofer Beharier
9
,
Gao-Wei Mao
1
,
Haider H Dar
1
,
Alexandr A Kapralov
1
,
Andrew A Amoscato
1
,
Teresa G Hastings
10
,
Timothy J Greenamyre
10
,
Charleen T Chu
11
,
Yoel Sadovsky
9
,
Ivet Bahar
5
,
Hülya Bayır
1,
6
,
Yulia Y Tyurina
1
,
Rong-Rong He
2,
3
,
Valerian E Kagan
1,
12,
13,
14,
15
Affiliation
Department of Environmental and Occupational Health and Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, China.
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MoE), College of Pharmacy, Jinan University, Guangzhou, China.
Institute of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University in Toruń, Toruń, Poland.
Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Critical Care Medicine, Safar Center for Resuscitation Research, Children's Neuroscience Institute, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA.
UCL Queen Square Institute of Neurology, Department of Clinical and Movement Neurosciences, University College London, Queen Square, London, UK.
Magee-Womens Research Institute and Department of OBGYN, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Institute of Regenerative Medicine, IM Sechenov Moscow State Medical University, Moscow, Russia.
Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal
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, PLA2G6 or PNPLA9 gene) 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 that PLA2G6 mutations 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-engineered Pnpla9R748W/R748W mice 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-mutant SncaA53T mice, 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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