PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals
Autor: | Vladimir A. Tyurin, Indira H. Shrivastava, Hülya Bayır, Gaowei Mao, David R. Emlet, Xiaoyan Wen, Andrew P. VanDemark, Simon C. Watkins, Theodore R. Holman, John A. Kellum, Tamil S. Anthonymuthu, Elizabeth M. Kenny, Alexandr A. Kapralov, Feng Qu, Valerian E. Kagan, Claudette M. St. Croix, Sally E. Wenzel, Ivet Bahar, Karolina Mikulska-Ruminska, Haider H. Dar, Yulia Y. Tyurina, Joel C. Rosenbaum, Louis J. Sparvero, Yoshinori Minami, Jinming Zhao, Qin Yang, Andrew A. Amoscato |
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Rok vydání: | 2017 |
Předmět: |
Models
Molecular 0301 basic medicine Scaffold protein Programmed cell death Lipoxygenase Regulator Apoptosis Phosphatidylethanolamine Binding Protein Biology GPX4 Article General Biochemistry Genetics and Molecular Biology Cell Line Mice 03 medical and health sciences Brain Injuries Traumatic medicine Animals Humans Protein kinase A Oxazolidinones Kidney Cell Death Drug discovery Acute Kidney Injury Asthma Cell biology Isoenzymes 030104 developmental biology medicine.anatomical_structure Biochemistry biology.protein Oxidation-Reduction |
Zdroj: | Cell. 171:628-641.e26 |
ISSN: | 0092-8674 |
Popis: | 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. |
Databáze: | OpenAIRE |
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