PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals

By Sally E. Wenzel, Y. Tyurina, Jinming Zhao, C. Croix, H. Dar, G. Mao, V. Tyurin, T. Anthonymuthu, A. Kapralov, A. Amoscato and 17 more. Cell, 2017

835 citations recorded by the source corpus.

SUMMARY Ferroptosis is a form of programmed cell death 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.

Subfields: Cancer Research, Pulmonary and Respiratory Medicine, Surgery

View Paper: https://www.semanticscholar.org/paper/7c99eb70dec4ae7f67b9b27ddd421c3729cebdfe

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. D. Tang
2. R. Kang
3. Guido Kroemer
4. Xuejun Jiang
5. Brent R. Stockwell
6. Qing-zhang Tuo
7. P. Lei
8. W. Gu

In Pulmonary and Respiratory Medicine

1. Brent R. Stockwell
2. D. Tang
3. R. Kang
4. Guido Kroemer
5. Jiao Liu
6. D. Klionsky
7. Xuejun Jiang
8. Qing-zhang Tuo

In Surgery

1. Brent R. Stockwell
2. D. Tang
3. R. Kang
4. Guido Kroemer
5. D. Klionsky

Citations in the corpus

• The cell biology of ferroptosis (2024, neutral): “It is controversial which mechanism is most important for ferroptosis and it seems likely that both mechanisms are relevant in one cell type or another 17–20 .”
• Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “74 78 Several ALOX inhibitors have been shown to possess antioxidant properties, effectively shielding cells from lipid peroxidation.”
• Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion (2019, background): “reported proteins such as PEBP1 [63], NCOA4 [64, 65],”
• Autophagy-Dependent Ferroptosis: Machinery and Regulation (2020, background): “The mammalian ALOX family, consisting of six members (ALOXE3, ALOX5, ALOX12, ALOX12B, ALOX15, and ALOX15B), plays a tissue- or cell-dependent role in the induction of ferroptosis (Hinman et al., 2018; Liu et al., 2015; Shintoku et al., 2017; Wenzel et al., 2017).”
• CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4 (2022, background): “Lysophosphatidylcholine acyltransferase 3 (LPCAT3) and lipoxygenases (LOX) are involved in the incorporation of arachidonyl-CoAs into phospholipids on membranes and oxidation of these phospholipids, respectively (Conrad and Pratt, 2019; Ingold et al., 2018; Wenzel et al., 2017).”
• Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications (2021, background): “, PUFA‐PE) is linked explicitly with ferroptosis.(230,244) PE PLs can assemble in a non‐bilayer arrangement(245) that facilitates pro‐ferroptotic oxidation of PUFA‐PE by 12/15‐LOX.”
• Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke. (2019, neutral): “, 2014), traumatic brain injury (Wenzel et al., 2017), and Parkinson’s disease (Do Van et al.”
• Ferroptosis: mechanisms and links with diseases (2021, background): “Whereas, phosphatidylethanolaminebinding protein 1 (PEBP1), a scaffold protein inhibitor of protein kinase cascade, combines with 15-Lox after it is dissociated from RAF1 kinase, shows high selectivity and specificity for ETE-PE and promotes ferroptosis by generation of lipid death signals.(12) NO•,”
• The molecular machinery of regulated cell death (2019, positive): “Phosphatidylethanolamine binding protein 1 (PEBP1, also known as RKIP), a scaffold protein inhibitor of protein kinase cascades, is required for the enzymatic activity of ALOX15 in ferroptosis.(142) The upregulation of ACSL4, but not other ACSL members, seems to be a marker of ferroptosis.”