1. Peroxiredoxin-2: A Novel Regulator of Iron Homeostasis in Ineffective Erythropoiesis
- Author
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Soo Young Choi, Anna Cozzi, Giorgia Federico, Sebastian Mueller, Davide Melisi, Tom Ganz, Narla Mohandas, Christophe Lebouef, Sonia Levi, Achille Iolascon, Luigia De Falco, Alberto Zamò, Francesca Carlomagno, I Silva, Mariasole Bruno, Dae Won Kim, Angela Siciliano, Enrica Federti, Carmine Carbone, Alessandro Matte, Anne Janin, Lucia De Franceschi, Matte, Alessandro, De Falco, Luigia, Federti, Enrica, Cozzi, Anna, Iolascon, Achille, Levi, Sonia, Mohandas, Narla, Zamo, Alberto, Bruno, Mariasole, Lebouef, Christophe, Janin, Anne, Siciliano, Angela, Ganz, Tom, Federico, Giorgia, Carlomagno, Francesca, Mueller, Sebastian, Silva, Ine, Carbone, Carmine, Melisi, Davide, Kim, Dae Won, Choi, Soo Young, De Franceschi, Lucia, and Levi, SONIA MARIA ROSA
- 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 - 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.
- Published
- 2017