PMID- 29053969
OWN - NLM
STAT- MEDLINE
DCOM- 20171101
LR  - 20181113
IS  - 1097-4172 (Electronic)
IS  - 0092-8674 (Print)
IS  - 0092-8674 (Linking)
VI  - 171
IP  - 3
DP  - 2017 Oct 19
TI  - PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death 
      Signals.
PG  - 628-641.e26
LID - S0092-8674(17)31138-8 [pii]
LID - 10.1016/j.cell.2017.09.044 [doi]
AB  - 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.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Wenzel, Sally E
AU  - Wenzel SE
AD  - Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department 
      of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: 
      wenzelse@upmc.edu.
FAU - Tyurina, Yulia Y
AU  - Tyurina YY
AD  - Department of Environmental and Occupational Health, Center for Free Radical and 
      Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Zhao, Jinming
AU  - Zhao J
AD  - Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - St Croix, Claudette M
AU  - St Croix CM
AD  - Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Dar, Haider H
AU  - Dar HH
AD  - Department of Environmental and Occupational Health, Center for Free Radical and 
      Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Mao, Gaowei
AU  - Mao G
AD  - Department of Critical Care Medicine, Center for Critical Care Nephrology, Safar 
      Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Tyurin, Vladimir A
AU  - Tyurin VA
AD  - Department of Environmental and Occupational Health, Center for Free Radical and 
      Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Anthonymuthu, Tamil S
AU  - Anthonymuthu TS
AD  - Department of Critical Care Medicine, Center for Critical Care Nephrology, Safar 
      Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Kapralov, Alexandr A
AU  - Kapralov AA
AD  - Department of Environmental and Occupational Health, Center for Free Radical and 
      Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Amoscato, Andrew A
AU  - Amoscato AA
AD  - Department of Environmental and Occupational Health, Center for Free Radical and 
      Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Mikulska-Ruminska, Karolina
AU  - Mikulska-Ruminska K
AD  - Department of Computational and System Biology, University of Pittsburgh, 
      Pittsburgh, PA, USA; Institute of Physics, Nicolaus Copernicus University, Torun, 
      Poland.
FAU - Shrivastava, Indira H
AU  - Shrivastava IH
AD  - 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.
FAU - Kenny, Elizabeth M
AU  - Kenny EM
AD  - Department of Critical Care Medicine, Center for Critical Care Nephrology, Safar 
      Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Yang, Qin
AU  - Yang Q
AD  - Department of Critical Care Medicine, Center for Critical Care Nephrology, Safar 
      Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Rosenbaum, Joel C
AU  - Rosenbaum JC
AD  - Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Sparvero, Louis J
AU  - Sparvero LJ
AD  - Department of Environmental and Occupational Health, Center for Free Radical and 
      Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Emlet, David R
AU  - Emlet DR
AD  - Department of Critical Care Medicine, Center for Critical Care Nephrology, Safar 
      Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Wen, Xiaoyan
AU  - Wen X
AD  - Department of Critical Care Medicine, Center for Critical Care Nephrology, Safar 
      Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Minami, Yoshinori
AU  - Minami Y
AD  - Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Qu, Feng
AU  - Qu F
AD  - Department of Environmental and Occupational Health, Center for Free Radical and 
      Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Watkins, Simon C
AU  - Watkins SC
AD  - Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Holman, Theodore R
AU  - Holman TR
AD  - Department of Chemistry and Biochemistry, University of California, Santa Cruz, 
      CA, USA.
FAU - VanDemark, Andrew P
AU  - VanDemark AP
AD  - Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Kellum, John A
AU  - Kellum JA
AD  - Department of Critical Care Medicine, Center for Critical Care Nephrology, Safar 
      Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Bahar, Ivet
AU  - Bahar I
AD  - Department of Computational and System Biology, University of Pittsburgh, 
      Pittsburgh, PA, USA.
FAU - Bayir, Hulya
AU  - Bayir H
AD  - 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.
FAU - Kagan, Valerian E
AU  - Kagan VE
AD  - 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.
LA  - eng
GR  - R01 ES020693/ES/NIEHS NIH HHS/United States
GR  - S10 OD021540/OD/NIH HHS/United States
GR  - U19 AI068021/AI/NIAID NIH HHS/United States
GR  - R01 NS076511/NS/NINDS NIH HHS/United States
GR  - R01 DK083961/DK/NIDDK NIH HHS/United States
GR  - U10 HL098177/HL/NHLBI NIH HHS/United States
GR  - R01 DK070910/DK/NIDDK NIH HHS/United States
GR  - P30 DA035778/DA/NIDA NIH HHS/United States
GR  - R01 NS061817/NS/NINDS NIH HHS/United States
GR  - P01 HL114453/HL/NHLBI NIH HHS/United States
GR  - P01 AI106684/AI/NIAID NIH HHS/United States
GR  - R01 GM097204/GM/NIGMS NIH HHS/United States
GR  - R01 AI040600/AI/NIAID NIH HHS/United States
GR  - U10 HL109152/HL/NHLBI NIH HHS/United States
GR  - U54 HG008540/HG/NHGRI NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Cell
JT  - Cell
JID - 0413066
RN  - 0 (Isoenzymes)
RN  - 0 (Oxazolidinones)
RN  - 0 (PEBP1 protein, human)
RN  - 0 (Phosphatidylethanolamine Binding Protein)
RN  - 0 (Raf kinase inhibitory protein, mouse)
RN  - 0 (locostatin)
RN  - EC 1.13.11.12 (Lipoxygenase)
SB  - IM
CIN - Cell. 2017 Oct 19;171(3):501-502. PMID: 29053966
MH  - Acute Kidney Injury/metabolism/*pathology
MH  - Animals
MH  - Apoptosis
MH  - Asthma/metabolism/*pathology
MH  - Brain Injuries, Traumatic/metabolism/*pathology
MH  - *Cell Death/drug effects
MH  - Cell Line
MH  - Humans
MH  - Isoenzymes/metabolism
MH  - Lipoxygenase/chemistry/metabolism
MH  - Mice
MH  - Models, Molecular
MH  - Oxazolidinones/pharmacology
MH  - Oxidation-Reduction
MH  - Phosphatidylethanolamine Binding Protein/chemistry/*metabolism
PMC - PMC5683852
MID - NIHMS912543
OTO - NOTNLM
OT  - GPX4
OT  - PEBP1/15LO complex
OT  - acute kidney injury
OT  - asthma
OT  - brain trauma
OT  - cell death
OT  - ferroptosis
OT  - ferrostatin-1
OT  - phosphatidylethanolamine oxidation
OT  - redox phospholipidomics
EDAT- 2017/10/21 06:00
MHDA- 2017/11/02 06:00
PMCR- 2018/10/19
CRDT- 2017/10/21 06:00
PHST- 2017/02/07 00:00 [received]
PHST- 2017/07/05 00:00 [revised]
PHST- 2017/09/25 00:00 [accepted]
PHST- 2017/10/21 06:00 [entrez]
PHST- 2017/10/21 06:00 [pubmed]
PHST- 2017/11/02 06:00 [medline]
PHST- 2018/10/19 00:00 [pmc-release]
AID - S0092-8674(17)31138-8 [pii]
AID - 10.1016/j.cell.2017.09.044 [doi]
PST - ppublish
SO  - Cell. 2017 Oct 19;171(3):628-641.e26. doi: 10.1016/j.cell.2017.09.044.