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Cited by 1,055Iron Metabolism and DisordersNeurological diseases and metabolismTrace Elements in Health

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

Rouault, Tracey A·2006·Nature Chemical Biology
DOI 10.1038/nchembio807
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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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Crossref · 10.1038/nchembio807

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  • The MIGA1 gene plays a major role for the development and proliferation of lymphocytes since defective T- and B-cell activation is caused by inadequate iron uptake.

    “This gene also plays a major role for the development and proliferation of lymphocyte since defective T- and B-cell activation is caused by inadequate iron uptake (Rouault, 2006; Jabara et al., 2016).”

    From Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed (2019) · cites this paper as Rouault, 2006

  • The MIGA1 gene is associated with iron deficiency anemia and immunity.

    “The MIGA1 gene is associated with iron deficiency anemia and immunity (Moura et al., 2001; Rouault, 2006).”

    From Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed (2019) · cites this paper as Rouault, 2006

  • When iron levels normalize, IRP1 regains its Fe-S cluster and aconitase activity, resulting in increased ferritin translation and decreased TFR expression, reducing Fe uptake.

    “When iron levels normalize again, IRP1 regains its Fe-S cluster and aconitase activity. This results in increased ferritin translation and decreased TFR expression, resulting in reduced Fe uptake (Li et al., 2004; Rouault, 2006; Leipuviene and Theil, 2007; Sanchez et al., 2011; Figure 2).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Rouault, 2006

  • Hyperferritinemia-cataract syndrome is caused by a mutation in the iron-responsive element of the FTL gene and is not associated with brain iron accumulation but with ferritin crystals in ocular lenses causing early adulthood cataracts.

    “Interestingly, the hyperferritinemia-cataract syndrome that is caused by a mutation in a specific non-coding region of the FTL gene, the iron-responsive element (IRE), is not associated with iron accumulation in the brain but with the formation of ferritin crystals in the ocular lenses, resulting in cataracts in early adulthood [23, 83, 195].”

    From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [195]

  • IRPs sense free labile iron and control cellular iron homeostasis at the post-transcriptional level by interacting with IREs in Tfr1, Dmt1, Fpn1, FTH, and FTL mRNAs, counterbalancing fluctuations in intracellular iron.

    “IRPs sense free labile iron and control cellular iron homeostasis at the post-transcriptional level: Due to their ability to interact with iron-responsive elements (IREs) that are present in the non-coding mRNA sequences of Tfr1, Dmt1, Fpn1, FTH, and FTL chains, fluctuations in intracellular iron are promptly counterbalanced [179, 195].”

    From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [195]

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Authors
Rouault, T. A.
Affiliations
National Institutes of Health (US)
Corresponding author
Rouault, Tracey A
ORCID
Rouault, Tracey A
Venue
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Published
2006-07-18
Volume
2
Issue
8
Pages
406-414
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
DOI
10.1038/nchembio807
OpenAlex
W1998351143
Cited by
1,055
References
108
Citations by year
2026: 38 · 2025: 47 · 2024: 60 · 2023: 54 · 2022: 57 · 2021: 71 · 2020: 39 · 2019: 59 · 2018: 43 · 2017: 53 · 2016: 40 · 2015: 64 · 2014: 73 · 2013: 36 · 2012: 63
FWCI
6.12
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
Keywords
iron regulatory proteins, iron regulatory protein 1, IRP2, iron homeostasis, iron-responsive element, post-transcriptional regulation, iron-sulfur clusters, aconitase, ubiquitin-proteasome degradation, iron deficiency, ferritin, transferrin receptor, hereditary hyperferritinemia-cataract syndrome, neurodegenerative diseases, anemia, embryonic lethality
MeSH terms
Iron Deficiencies, Animals, Cataract, Ferritins, Homeostasis, Humans, Iron, Mutation, Protein Conformation, RNA, Messenger, Syndrome, Iron Metabolism Disorders, Response Elements, Iron-Regulatory Proteins

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