PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals
- PMID: 29053969
- PMCID: PMC5683852
- DOI: 10.1016/j.cell.2017.09.044
PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals
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.
Copyright © 2017 Elsevier Inc. All rights reserved.
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Comment in
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Transforming Lipoxygenases: PE-Specific Enzymes in Disguise.Cell. 2017 Oct 19;171(3):501-502. doi: 10.1016/j.cell.2017.10.006. Cell. 2017. PMID: 29053966 Free PMC article.
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References
-
- Banfield MJ, Barker JJ, Perry AC, Brady RL. Function from structure? The crystal structure of human phosphatidylethanolamine-binding protein suggests a role in membrane signal transduction. Structure. 1998;6:1245–1254. - PubMed
-
- Banthiya S, Kalms J, Galemou Yoga E, Ivanov I, Carpena X, Hamberg M, Kuhn H, Scheerer P. Structural and functional basis of phospholipid oxygenase activity of bacterial lipoxygenase from Pseudomonas aeruginosa. Biochim Biophys Acta. 2016;1861:1681–1692. - PubMed
-
- Bayir H, Kagan VE, Tyurina YY, Tyurin V, Ruppel RA, Adelson PD, Graham SH, Janesko K, Clark RS, Kochanek PM. Assessment of antioxidant reserves and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatr Res. 2002;51:571–578. - PubMed
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