title: Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors.
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.
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany;
authors.forename: Özge
authors.initials: Ö
authors.lastname: Canli
authors.affiliation: Institute of Clinical Chemistry, Klinikum rechts der Isar, Technical University Munich, Munich, Germany;
authors.forename: Yasemin B
authors.initials: YB
authors.lastname: Alankuş
authors.affiliation: Department of Molecular Biomedical Research, VIB, VIB-Ghent University, Ghent (Zwijnaarde), Belgium;
authors.forename: Sasker
authors.initials: S
authors.lastname: Grootjans
authors.affiliation: Institute of Experimental Cancer Research, Comprehensive Cancer Center and University Hospital Ulm, Ulm, Germany;
authors.forename: Naidu
authors.initials: N
authors.lastname: Vegi
authors.affiliation: Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, Munich, Germany; and.
authors.forename: Lothar
authors.initials: L
authors.lastname: Hültner
authors.affiliation: Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology in Zurich, Basel, Switzerland.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Hoppe
authors.affiliation: Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology in Zurich, Basel, Switzerland.
authors.forename: Timm
authors.initials: T
authors.lastname: Schroeder
authors.affiliation: Department of Molecular Biomedical Research, VIB, VIB-Ghent University, Ghent (Zwijnaarde), Belgium;
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.affiliation: Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, Munich, Germany; and.
authors.forename: Georg W
authors.initials: GW
authors.lastname: Bornkamm
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany;
authors.forename: Florian R
authors.initials: FR
authors.lastname: Greten
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D041905:Erythroid Cells / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D005979:Glutathione Peroxidase / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D018384:Oxidative Stress; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D017382:Reactive Oxygen Species; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse