Iron Metabolism and the IRE/IRP Regulatory System: An Update

Cellular iron homeostasis is accomplished by the coordinated regulated expression of the transferrin receptor and ferritin, which mediate iron uptake and storage, respectively. The mechanism is posttranscriptional and involves two cytoplasmic iron regulatory proteins, IRP1 and IRP2. Under conditions of iron starvation, IRPs stabilize the transferrin receptor and inhibit the translation of ferritin mRNAs by binding to "iron responsive elements" (IREs) within their untranslated regions. The IRE/IRP system also controls the expression of additional IRE-containing mRNAs, encoding proteins of iron and energy metabolism. The activities of IRP1 and IRP2 are regulated by distinct posttranslational mechanisms in response to cellular iron levels. Thus, in iron-replete cells, IRP1 assembles a cubane iron-sulfur cluster, which prevents IRE binding, while IRP2 undergoes proteasomal degradation. IRP1 and IRP2 also respond, albeit differentially, to iron-independent signals, such as hydrogen peroxide, hypoxia, or nitric oxide. Basic principles of the IRE/IRP system and recent advances in understanding the regulation and the function of IRP1 and IRP2 are discussed.