Rouault, T. A. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat. Chem. Biol. 2, 406-414

Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Building 18T, Room 101, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature Chemical Biology (Impact Factor: 13). 09/2006; 2(8):406-14. DOI: 10.1038/nchembio807
Source: PubMed


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.

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    • "Free iron (Fe 2+ or Fe 3+ ) is toxic even at concentrations below 10 −18 M because it promotes oxidative damage inside cells [7] [8]. However, the ferric ion is contained in the catalytic site of many proteins and enzymes for structural purposes [9] [10] [11] [12]. The formation of ferrihemoglobin (methemoglobin), which cannot bind to oxygen, is induced by the oxidation of heme iron to ferric ion [13]. "
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    • "In the absence of iron, IRP1 and IRP2 bind to iron responsive elements (IREs) present in the 5 0 or 3 0 untranslated regions (UTRs) of the mRNAs encoding these proteins. This binding prevents or promotes translation of the encoded proteins (Hentze et al., 2010; Muckenthaler et al., 2008; Rouault, 2006). For example, the translation of the iron storage protein ferritin is regulated by IRP binding to an IRE present in the 5 0 UTR of the mRNA (Hentze et al., 1987). "
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    • "The biogenesis of this ISC within IRP1 occurs within the cytosolic ISC biogenesis (CIA) pathway, and is directly regulated by the activity of the 'CIA targeting complex', formed by the CIA ISC targeting proteins, CIA1, CIA2A and MMS19[110]. The acquisition of this (4Fe-4S) cluster converts IRP1 into a cytosolic aconitase, and thus IRP1's conversion to the ISC-containing form is dependent on active ISC biogenesis in the mitochondria and/or the cytosol[109]. IRP2 is unable to acquire an ISC[111], and it is instead regulated at the level of protein abundance by proteasomal degradation via the IRP2-targeting E3 ubiquitin ligase subunit, F-box and leucine-rich repeat protein 5 (FBXL5); a protein which itself is regulated at the level of protein stability by iron and oxygen[112,113]. For recent reviews of the IRP/IRE system in iron homeostasis, see114115116. "
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