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The IRP1-HIF-2α Axis Coordinates Iron and Oxygen Sensing with Erythropoiesis and Iron Absorption

2013; Cell Press; Volume: 17; Issue: 2 Linguagem: Inglês

10.1016/j.cmet.2013.01.007

1932-7420

Sheila A. Anderson, Christopher P. Nizzi, Yuan-I Chang, Kathryn M. Deck, Paul J. Schmidt, Bruno Galy, Alisa Damnernsawad, Aimee Teo Broman, Christina Kendziorski, Matthias W. Hentze, Mark D. Fleming, Jing Zhang, Richard S. Eisenstein,

Hemoglobinopathies and Related Disorders

Red blood cell production is a finely tuned process that requires coordinated oxygen- and iron-dependent regulation of cell differentiation and iron metabolism. Here, we show that translational regulation of hypoxia-inducible factor 2α (HIF-2α) synthesis by iron regulatory protein 1 (IRP1) is critical for controlling erythrocyte number. IRP1-null (Irp1−/−) mice display a marked transient polycythemia. HIF-2α messenger RNA (mRNA) is derepressed in kidneys of Irp1−/− mice but not in kidneys of Irp2−/− mice, leading to increased renal erythropoietin (Epo) mRNA and inappropriately elevated serum Epo levels. Expression of the iron transport genes DCytb, Dmt1, and ferroportin, as well as other HIF-2α targets, is enhanced in Irp1−/− duodenum. Analysis of mRNA translation state in the liver revealed IRP1-dependent dysregulation of HIF-2α mRNA translation, whereas IRP2 deficiency derepressed translation of all other known 5′ iron response element (IRE)-containing mRNAs expressed in the liver. These results uncover separable physiological roles of each IRP and identify IRP1 as a therapeutic target for manipulating HIF-2α action in hematologic, oncologic, and other disorders.