The role of iron regulatory proteins in mammalian iron homeostasis and disease

Abstract

Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are mammalian proteins that register cytosolic iron concentrations and post-transcriptionally regulate expression of iron metabolism genes to optimize cellular iron availability. In iron-deficient cells, IRPs bind to iron-responsive elements (IREs) found in the mRNAs of ferritin, the transferrin receptor and other iron metabolism transcripts, thereby enhancing iron uptake and decreasing iron sequestration. IRP1 registers cytosolic iron status mainly through an iron-sulfur switch mechanism, alternating between an active cytosolic aconitase form with an iron-sulfur cluster ligated to its active site and an apoprotein form that binds IREs. Although IRP2 is homologous to IRP1, IRP2 activity is regulated primarily by iron-dependent degradation through the ubiquitin-proteasomal system in iron-replete cells. Targeted deletions of IRP1 and IRP2 in animals have demonstrated that IRP2 is the chief physiologic iron sensor. The physiological role of the IRP-IRE system is illustrated by (i) hereditary hyperferritinemia cataract syndrome, a human disease in which ferritin L-chain IRE mutations interfere with IRP binding and appropriate translational repression, and (ii) a syndrome of progressive neurodegenerative disease and anemia that develops in adult mice lacking IRP2. The early death of mouse embryos that lack both IRP1 and IRP2 suggests a central role for IRP-mediated regulation in cellular viability.

Redox control of iron regulatory protein 2 stability

“…2B). These responses are consistent with stabilization of TfR1 mRNA and translational inhibition of ferritin mRNA by activated IRP2 [1][2][3]; the increase of TfR1 expression is also congruous with the reported IRP-independent stimulation of TfR1 mRNA translation that is elicited during mild sustained oxidative stress [28]. As the catabolism of H 2 O 2 by catalases is associated with generation of oxygen [22], the degradation of a 1 mM H 2 O 2 bolus may lead to hyperoxia, which would be expected to upregulate FBXL5 and antagonize the stabilization of IRP2.…”

“…We then evaluated the effects of H 2 O 2 -mediated stabilization of IRP2 in the expression of two known IRP downstream targets, ferritin and transferrin receptor 1 (TfR1). Ferritin, an iron storage protein, is negatively regulated by IRPs at the translational level, while TfR1, the protein involved in the uptake of transferrin-bound iron from circulation, is positively regulated by IRPs at the level of mRNA stability [1][2][3]. The stabilization of IRP2 by H 2 O 2 (Fig.…”

Evaluating the effectiveness of transferrin receptor‐1 (TfR1) as a magnetic resonance reporter gene

“…Overexpression of the TfR1 transgene led to a decrease in endogenous TfR1 mRNA levels. This was not unexpected because the 3′ untranslated region (UTR) of the endogenous TfR1 mRNA contains five iron responsive elements (IREs), which ensures that the mRNA is degraded when intracellular iron concentrations are high 24, 25, 26. To prevent the TfR1 transgene from being regulated by this negative feedback loop, we used the previously described strategy of deleting the IREs from the 3′UTR, which enables high levels of the exogenous TfR1 mRNA to accumulate in the cells 11, 19.…”

The role of lysosomes in iron metabolism and recycling

“…The iron regulatory proteins 1 and 2 (IRP1 and IRP2) control the uptake and storage of iron at the cellular level by interacting at the translational level with ironresponsive elements (IREs) on RNA transcripts that code for the H-and L-ferritin subunits, TfR1, DMT1, mitochondrial aconitase and 5-aminolevulinate synthase (Hentze et al, 2010, Rouault, 2006. Depending on their degree of iron binding, IRPs attach themselves to IREs and thereby prevent or stabilize translation of the above proteins that regulate uptake, storage, transport and metabolism of intracellular iron.…”