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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    ABSTRACT: A novel ethylenediamine derivative of a rhodamine 6G silica particle (RSSP) was covalently grafted onto the surface of mesoporous silica to create a fluorescent chemosensing hybrid material for the detection of Fe3+. The prepared RSSP was dispersed in water, and its optical sensing response to various metal cations (Ag+, Na+, Li+, K+, Cs+, Hg2+, Cu2+, Ca2+, Cd2+, Co2+, Fe2+, Mg2+, Ni2+, Pb2+, Zn2+, Fe3+ and Al3+) was evaluated through the resulting fluorescence spectra. Upon coordination with Fe3+, the promoted ring opening of the rhodamine spirolactam ring in the RSSP activated a fluorescence response via CHEF (chelation enhancement fluorescence). This fluorescence enhancement was induced by the spirolactam ring system of the chemosensor immobilized in the pore. Conversely, the fluorescence response of the RSSP-Fe3+ complex was quenched by the addition of EDTA, which abstracted the Fe3+ ion from the complex and turned the sensor off, confirming that the recognition process was reversible. The proposed chemosensor also exhibited excellent selectivity for Fe3+ over competing environmentally relevant metal ions. The chemosensor can also be used over a wide pH range and was readily regenerated. The sensing ability of RSSP makes it desirable for practical applications in microfluidics analysis tools, intracellular bio-imaging and lab-on-a-chip development.
    Sensors and Actuators B Chemical 03/2016; 224:404-412. DOI:10.1016/j.snb.2015.10.058 · 4.10 Impact Factor
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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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    ABSTRACT: During its parasitic life stages, the marine ectoparasitic copepod Lepeophtheirus salmonis ingests large amounts of host blood, which contains high amounts of iron. Iron is an essential micronutrient, but also toxic in high dosages, and blood-feeding parasites like the salmon louse must thus possess an efficient system to handle the excess iron. Iron regulatory protein 1 and 2 (IRP1 and IRP2) are known to play crucial roles in this process, by regulating several proteins involved in iron transport and storage, depending on the cellular iron concentration. To gain knowledge about the regulation of the iron metabolism in salmon lice, two IRP homologues (LsIRP1A and LsIRP1B) were identified by sequence and predicted structure similarity to known IRPs in other species. In situ hybridisation revealed that LsIRP1A and LsIRP1B mRNAs were expressed in the ovaries, oviducts and vitellogenic oocytes of adult females. Transcription levels of LsIRP1A and LsIRP1B mRNAs did not differ significantly between the different developmental stages of the salmon louse. Adults in the absence of blood as a feed source had decreased levels of LsIRP1A, but not LsIRP1B mRNA. RNA binding experiments indicated the presence of functioning IRP in salmon lice. In order to explore the biological functions of LsIRP1A and LsIRP1B, the mRNAs of both proteins were knocked down by RNA interference (RNAi) in preadult females. The knockdown was confirmed by qRT-PCR. LsIRP1B knockdown lice produced less offspring than control lice due to slightly shorter egg strings and had decreased levels of transcripts involved in egg development. Knockdown of both LsIRP1A and LsIRP1B caused increased expression of a salmon louse Ferritin (LsFer). These results confirm that salmon lice have two IRP1 homologues, LsIRP1A and LsIRP1B, and might suggest a function in cellular iron regulation in the reproductive organs and eggs. Copyright © 2015. Published by Elsevier Inc.
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    • "Low cytosolic iron levels cause two homologous IRPs (IRP1 and IRP2) to inhibit Ft and Fpn-1 translation and to stabilize mRNA transcripts of TfR and divalent metal transporter 1 (DMT1) [26]. In iron replete cells, neither IRP1 nor IRP2 binds IREs and Ft/Fpn-1 expression increases while TfR/DMT1 expression decreases [27]. After SAH, a large amount of iron arising from hemoglobin degradation was released into the subarachnoid space and more iron was transported into the cells. "
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