IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2α mRNA translation

Hypoxia inducible factor 2 alpha (HIF2 alpha) transcriptionally activates several genes in response to hypoxia. Under normoxic conditions, it undergoes oxygen-dependent degradation by the prolyl hydroxylase (PHD)/von Hippel-Lindau (VHL) system. The presence of an iron-responsive element (IRE) within the 59 untranslated region of HIF2 alpha mRNA suggests a further iron-and oxygen-dependent mechanism for translational regulation of its expression via iron regulatory proteins 1 and 2 (IRP1 and IRP2, respectively). We show here that the disruption of mouse IRP1, but not IRP2, leads to profound HIF2 alpha-dependent abnormalities in erythropoiesis and systemic iron metabolism. Thus, 4- to 6-week-old IRP1(-/-) mice exhibit splenomegaly and extramedullary hematopoiesis, which is corrected in older animals. These erythropoietic abnormalities are caused by translational de-repression of HIF2 alpha mRNA and subsequent accumulation of HIF2 alpha, which induces expression of erythropoietin (Epo). Increased levels of circulating Epo lead to reticulocytosis, polycythemia, and suppression of hepatic hepcidin mRNA. This in turn promotes hyperferremia and iron depletion in splenic macrophages due to unrestricted expression of ferroportin. Our data demonstrate that IRP1 is the principal regulator of HIF2 alpha mRNA translation in vivo and provide evidence that translational control of HIF2 alpha expression dominates over PHD/VHL-mediated regulation of HIF2 alpha stability in juvenile IRP1(-/-) mice.