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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.

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Figure 1: Ferritin translation and TfR mRNA degradation are regulated by IRP binding.
Figure 2: IRE secondary structure.
Figure 3: Mutations of the ferritin L-chain IRE cause HHCS.
Figure 4: The iron-sulfur switch of IRP1.
Figure 5: Proposed schematic of mammalian iron-sulfur cluster assembly.
Figure 6: IRP2 has greater IRE-binding activity than IRP1 at the characteristically low oxygen concentrations found in mammalian tissues.
Figure 7: Neurodegeneration in adult IRP2−/− and IRP1+/− IRP2−/− animals is characterized by ferric iron accumulations in distinctive white-matter areas of the brain and by axonal degeneration in the affected white-matter areas.

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Acknowledgements

I thank J. Dupuy for drawing the figure of IRP1, modeling the IRP1-IRE interaction and generously sharing his insights about IRP1 structure, W.H. Tong for creating the iron-sulfur cluster biogenesis schematic and my scientific colleagues for their excellent work and help. This work was supported by the intramural program of the National Institute of Child Health and Human Development.

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Rouault, T. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol 2, 406–414 (2006). https://doi.org/10.1038/nchembio807

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