The physiological functions of iron regulatory proteins in iron homeostasis - an update

Abstract

Iron regulatory proteins (IRPs) regulate the expression of genes involved in iron metabolism by binding to RNA stem-loop structures known as iron responsive elements (IREs) in target mRNAs. IRP binding inhibits the translation of mRNAs that contain an IRE in the 5'untranslated region of the transcripts, and increases the stability of mRNAs that contain IREs in the 3'untranslated region of transcripts. By these mechanisms, IRPs increase cellular iron absorption and decrease storage and export of iron to maintain an optimal intracellular iron balance. There are two members of the mammalian IRP protein family, IRP1 and IRP2, and they have redundant functions as evidenced by the embryonic lethality of the mice that completely lack IRP expression (Irp1 (-/-)/Irp2(-/-) mice), which contrasts with the fact that Irp1 (-/-) and Irp2 (-/-) mice are viable. In addition, Irp2 (-/-) mice also display neurodegenerative symptoms and microcytic hypochromic anemia, suggesting that IRP2 function predominates in the nervous system and erythropoietic homeostasis. Though the physiological significance of IRP1 had been unclear since Irp1 (-/-) animals were first assessed in the early 1990s, recent studies indicate that IRP1 plays an essential function in orchestrating the balance between erythropoiesis and bodily iron homeostasis. Additionally, Irp1 (-/-) mice develop pulmonary hypertension, and they experience sudden death when maintained on an iron-deficient diet, indicating that IRP1 has a critical role in the pulmonary and cardiovascular systems. This review summarizes recent progress that has been made in understanding the physiological roles of IRP1 and IRP2, and further discusses the implications for clinical research on patients with idiopathic polycythemia, pulmonary hypertension, and neurodegeneration.

Keywords: erythropoiesis; iron metabolism; iron regulatory protein; iron responsive element; polycythemia; pulmonary hypertension.

FIGURE 1

The physiological effect of IRP2 deficiency in vivo. IRP2 is the predominant IRP protein in erythroblasts and neurons. According to intracellular iron status, IRP2 protein levels are regulated by the FBXL5-dependent proteasomal degradation pathway. By binding to the IREs in target transcripts of iron metabolism genes, IRP2 increases the expression of iron importers TfR1 and DMT1, and decreases the expression of the iron storage protein, ferritin, the iron exporter FPN1, and some iron utilization-related genes including ACO2 and eALAS, as well as other potential target genes, to maintain optimal intracellular iron levels. In erythroblasts, IRP2 deficiency decreases the expression of TfR1, resulting in insufficient import of iron by the Tf/TfR1 cycle to support heme biosynthesis, and derepresses eALAS expression, leading to protoporphyrin IX accumulation and microcytic hypochromic anemia. In neurons, IRP2 deficiency decreases the expression of the iron importer TfR1 and increases the expression of the ferritin. The accumulation of iron by ferritin depletes biologically available iron from the cytosol and leads to functional iron deficiency, mitochondrial dysfunction and neuronal degradation.

FIGURE 2

The scheme of physiological significance of IRP1 in vivo. IRP1 is the predominant IRP protein in renal interstitial fibroblasts and pulmonary endothelial cells. In iron-replete conditions, IRP1 ligates an iron–sulfur cluster and displays cytosolic aconitase activity; in iron-depleted conditions, IRP1 loses its iron–sulfur cluster and binds to IREs of target mRNAs to regulate expression of iron metabolism related genes. By binding to the 5′IRE of HIF2α mRNA, IRP1 regulates HIF2α expression according to iron and oxygen status, and thereby fine-tunes the levels of HIF2α protein in cooperation with prolyl hydroxylases and the Von Hippel–Lindau mediated proteasomal degradation pathway. In hypoxia or iron deficiency conditions, HIF2α protein is stabilized due to inactivation of prolyl hydroxylases, and then translocates to nucleus and transcriptionally increase erythropoietin (EPO) expression. Circulating through blood, EPO binds to EPO receptors on erythroblasts and stimulates erythroblasts to produce red blood cells (RBC), a process that consumes large amount of iron. When too much iron is consumed and systemic iron levels are low, IRP1 will be activated to reduce HIF2α expression and restrict RBC production. By this feedback mechanism, IRP1 regulates the balance between systemic iron homeostasis and erythropoiesis. In pulmonary endothelial cells, IRP1 regulates HIF2α translation and subsequently regulates the expression of endothelin-1 (ET-1), a peptide hormone that regulates pulmonary vascular contraction and the proliferation of smooth muscle cells, cardiomyocytes, and fibroblasts. Though the exact mechanism remains to be elucidated, IRP1 deficiency causes pulmonary hypertension and cardiovascular diseases in mice likely by derepression of HIF2α expression, increase of ET-1 levels and most probably other HIF2α targets also.