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Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors.
Blood 127, 139-148 (2016)
Maintaining cellular redox balance is vital for cell survival and tissue homoeostasis since imbalanced production of ROS may lead to oxidative stress and cell death. The anti-oxidant 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 it is essential for preventing RIP3 dependent necroptosis in erythroid precursor cells. Absence of Gpx4 leads to functional inactivation of caspase 8 by glutathionylation. This results in necroptosis, which occurs independently of TNFα activation. While 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 so far unrecognized unconventional upstream signaling activators of RIP3-dependent necroptosis.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Gpx4 Is Essential For Preventing Anemia In Mice Via Inhibiting Rip3-dependent Necroptosis In Erythroid Precursor Cells ; Ros Accumulation And Lipid Peroxidation In Erythroid Precursor Cells Trigger Receptor-independent Activation Of Necroptosis; Tumor-necrosis-factor; Cell-death; Programmed Necrosis; Hydrogen-peroxide; Inflammation; Apoptosis; Mice; Homeostasis; Ferroptosis; Protects
Language
english
Publication Year
2016
Prepublished in Year
2015
HGF-reported in Year
2015
ISSN (print) / ISBN
0006-4971
e-ISSN
1528-0020
Journal
Blood
Quellenangaben
Volume: 127,
Issue: 1,
Pages: 139-148
Publisher
American Society of Hematology
Publishing Place
Washington
Reviewing status
Peer reviewed
Institute(s)
Institute of Stem Cell Research (ISF)
Institute of Clinical Molecular Biology and Tumor Genetics (K.MOLBI)
Institute of Clinical Molecular Biology and Tumor Genetics (K.MOLBI)
POF-Topic(s)
30204 - Cell Programming and Repair
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s)
Stem Cell and Neuroscience
Immune Response and Infection
Immune Response and Infection
PSP Element(s)
G-500800-001
G-501400-006
G-501490-001
G-501400-005
G-501400-006
G-501490-001
G-501400-005
WOS ID
WOS:000369281300023
Scopus ID
84955476379
PubMed ID
26463424
Erfassungsdatum
2015-11-04