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Blood. 2016 Jan 7;127(1):139-48. doi: 10.1182/blood-2015-06-654194. Epub 2015 Oct 13.

Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors.

Author information

1
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany;
2
Institute of Clinical Chemistry, Klinikum rechts der Isar, Technical University Munich, Munich, Germany;
3
Department of Molecular Biomedical Research, VIB, VIB-Ghent University, Ghent (Zwijnaarde), Belgium;
4
Institute of Experimental Cancer Research, Comprehensive Cancer Center and University Hospital Ulm, Ulm, Germany;
5
Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, Munich, Germany; and.
6
Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology in Zurich, Basel, Switzerland.

Abstract

Maintaining cellular redox balance is vital for cell survival and tissue homoeostasis because imbalanced production of reactive oxygen species (ROS) may lead to oxidative stress and cell death. The antioxidant enzyme glutathione peroxidase 4 (Gpx4) is a key regulator of oxidative stress-induced cell death. We show that mice with deletion of Gpx4 in hematopoietic cells develop anemia and that Gpx4 is essential for preventing receptor-interacting protein 3 (RIP3)-dependent necroptosis in erythroid precursor cells. Absence of Gpx4 leads to functional inactivation of caspase 8 by glutathionylation, resulting in necroptosis, which occurs independently of tumor necrosis factor α activation. Although genetic ablation of Rip3 normalizes reticulocyte maturation and prevents anemia, ROS accumulation and lipid peroxidation in Gpx4-deficient cells remain high. Our results demonstrate that ROS and lipid hydroperoxides function as not-yet-recognized unconventional upstream signaling activators of RIP3-dependent necroptosis.

PMID:
26463424
PMCID:
PMC4705604
DOI:
10.1182/blood-2015-06-654194
[Indexed for MEDLINE]
Free PMC Article

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