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Cell. 2017 Oct 19;171(3):628-641.e26. doi: 10.1016/j.cell.2017.09.044.

PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals.

Author information

1
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: wenzelse@upmc.edu.
2
Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
3
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
4
Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA.
5
Department of Critical Care Medicine, Center for Critical Care Nephrology, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
6
Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, PA, USA; Institute of Physics, Nicolaus Copernicus University, Torun, Poland.
7
Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, PA, USA.
8
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
9
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, USA.
10
Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, PA, USA.
11
Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Critical Care Medicine, Center for Critical Care Nephrology, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA; Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA. Electronic address: bayihx@ccm.upmc.edu.
12
Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, 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; Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: kagan@pitt.edu.

Abstract

Ferroptosis is a form of programmed cell death that is pathogenic to several acute and chronic diseases and executed via oxygenation of polyunsaturated phosphatidylethanolamines (PE) by 15-lipoxygenases (15-LO) that normally use free polyunsaturated fatty acids as substrates. Mechanisms of the altered 15-LO substrate specificity are enigmatic. We sought a common ferroptosis regulator for 15LO. We discovered that PEBP1, a scaffold protein inhibitor of protein kinase cascades, complexes with two 15LO isoforms, 15LO1 and 15LO2, and changes their substrate competence to generate hydroperoxy-PE. Inadequate reduction of hydroperoxy-PE due to insufficiency or dysfunction of a selenoperoxidase, GPX4, leads to ferroptosis. We demonstrated the importance of PEBP1-dependent regulatory mechanisms of ferroptotic death in airway epithelial cells in asthma, kidney epithelial cells in renal failure, and cortical and hippocampal neurons in brain trauma. As master regulators of ferroptotic cell death with profound implications for human disease, PEBP1/15LO complexes represent a new target for drug discovery.

KEYWORDS:

GPX4; PEBP1/15LO complex; acute kidney injury; asthma; brain trauma; cell death; ferroptosis; ferrostatin-1; phosphatidylethanolamine oxidation; redox phospholipidomics

PMID:
29053969
PMCID:
PMC5683852
[Available on 2018-10-19]
DOI:
10.1016/j.cell.2017.09.044
[Indexed for MEDLINE]

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