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Peroxiredoxin-2: A Novel Regulator of Iron Homeostasis in Ineffective Erythropoiesis
- Source :
- Antioxidants & redox signalling 28 (2018): 1–14. doi:10.1089/ars.2017.7051, info:cnr-pdr/source/autori:Matte A.; De Falco L.; Federti E.; Cozzi A.; Iolascon A.; Levi S.; Mohandas N.; Zamo A.; Bruno M.; Lebouef C.; Janin A.; Siciliano A.; Ganz T.; Federico G.; Carlomagno F.; Mueller S.; Silva I.; Carbone C.; Melisi D.; Kim D.W.; Choi S.Y.; De Franceschi L./titolo:Peroxiredoxin-2: A Novel Regulator of Iron Homeostasis in Ineffective Erythropoiesis/doi:10.1089%2Fars.2017.7051/rivista:Antioxidants & redox signalling/anno:2018/pagina_da:1/pagina_a:14/intervallo_pagine:1–14/volume:28
- Publication Year :
- 2017
-
Abstract
- Aims: Iron overload (IO) is a life-threatening complication of chronic hemolytic disorders such as ?-thalassemia. IO results in severe cellular oxidative damage, leading to organ failure. Peroxiredoxin-2 (Prx2), a typical 2-cysteine-(Cys)-peroxiredoxin, is an important component of the cytoprotective system, but its response to IO is still to be fully defined. Results: We studied the effects of IO on Prx2-knockout mice (Prx2-/-). The absence of Prx2 enhanced toxicity due to IO on erythropoiesis. We found that IO failed to induce the typical hepcidin (Hamp) upregulation in Prx2-/- mice due to its failure to activate the signal transducer and activator of transcription-3 (STAT3) with intact Jak2 signaling. In Prx2-/- mice, the loss of Hamp response was also observed after administration of a single dose of oral iron. When lipopolysaccharide (LPS) was used to explore IL6-STAT3 activation in Prx2-/- mice, STAT3 activation and Hamp upregulation were once again defective. Treatment with PEP-fusion-recombinant-Prx2 (PEP Prx2) significantly increased STAT3 activation with upregulation of Hamp expression in both IO- and LPS-exposed Prx2-/- mice. We also confirmed the beneficial effects of PEP Prx2 on Hamp expression through STAT3 activation in ?-thalassemic mice. Innovation: We propose that Prx2 plays a key role in responding to cytotoxicity of IO, directly targeting STAT3-transcriptional factor in a Jak2-independent fashion and regulating Hamp in response to canonical stimuli. Conclusion: Collectively, our data highlight a novel role of Prx2 in iron homeostasis. Prx2 is a key cytoprotector against IO that is induced either by iron supplementation or due to chronic hemolysis as in ?-thalassemia. Prx2 is required to support STAT3 transcriptional activity and regulation of Hamp expression. Antioxid. Redox Signal. 28, 1-14.
- Subjects :
- 0301 basic medicine
Ineffective erythropoiesis
Physiology
Clinical Biochemistry
Hepcidin
medicine.disease_cause
Biochemistry
Mice
Peroxiredoxin-2
Bone Marrow
Homeostasis
Erythropoiesis
STAT3
General Environmental Science
Mice, Knockout
Anemia
chronic hemolytic disorders
Recombinant Proteins
Iron-overload (IO)
Liver
Peroxiredoxin-2 (Prx2)
β-thalassemia
HAMP
chronic hemolytic disorders, Iron-overload (IO), β-thalassemia, Peroxiredoxin-2 (Prx2)
Signal Transduction
STAT3 Transcription Factor
medicine.medical_specialty
Iron Overload
Iron
Peroxiredoxin 2
Biology
Models, Biological
hepcidin
iron overload
peroxiredoxin-2
03 medical and health sciences
Downregulation and upregulation
Hepcidins
Internal medicine
medicine
Animals
Molecular Biology
Cell Biology
Peroxiredoxins
Disease Models, Animal
Oxidative Stress
030104 developmental biology
Endocrinology
Gene Expression Regulation
Cytoprotection
biology.protein
General Earth and Planetary Sciences
Peroxiredoxin
Transcription Factors
Subjects
Details
- ISSN :
- 15577716
- Volume :
- 28
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Antioxidantsredox signaling
- Accession number :
- edsair.doi.dedup.....767265da0637e78eddb0ac741f21c5ce