PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals

• Published in: Cell 2017-10, Vol.171 (3), p.628-641.e26
• Main Authors: Wenzel, Sally E., Tyurina, Yulia Y., Zhao, Jinming, St. Croix, Claudette M., Dar, Haider H., Mao, Gaowei, Tyurin, Vladimir A., Anthonymuthu, Tamil S., Kapralov, Alexandr A., Amoscato, Andrew A., Mikulska-Ruminska, Karolina, Shrivastava, Indira H., Kenny, Elizabeth M., Yang, Qin, Rosenbaum, Joel C., Sparvero, Louis J., Emlet, David R., Wen, Xiaoyan, Minami, Yoshinori, Qu, Feng, Watkins, Simon C., Holman, Theodore R., VanDemark, Andrew P., Kellum, John A., Bahar, Ivet, Bayır, Hülya, Kagan, Valerian E.
• Format: Article
• Language: English
• Subjects: acute kidney injury; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Animals; Apoptosis; asthma; Asthma - metabolism; Asthma - pathology; Brain Injuries, Traumatic - metabolism; Brain Injuries, Traumatic - pathology; brain trauma; cell death; Cell Death - drug effects; Cell Line; ferroptosis; ferrostatin-1; GPX4; Humans; Isoenzymes - metabolism; Lipoxygenase - chemistry; Lipoxygenase - metabolism; Mice; Models, Molecular; Oxazolidinones - pharmacology; Oxidation-Reduction; PEBP1/15LO complex; Phosphatidylethanolamine Binding Protein - chemistry; Phosphatidylethanolamine Binding Protein - metabolism; phosphatidylethanolamine oxidation; redox phospholipidomics
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.09.044

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. [Display omitted] •A new pro-ferroptotic role for an old actor, PEBP1—catalytic reshuffle of 15LO•Epithelial redox phospholipoxysome oxidizes unsaturated phosphatidylethanolamines•PEBP1 and GPX4 are master regulators of ferroptosis in diverse epithelial cells•PEBP1/15LO-driven ferroptosis occurs in asthma, kidney injury, and brain trauma The small scaffolding protein PEBP1 regulates ferroptotic cell death by binding with lipoxygenases and allowing them to generate lipid peroxides.