The DOI matches its Crossref record; 108 of the 108 references it cites were found in a registry or an index.
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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“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“One such mechanism to maintain cytosolic iron levels are the iron regulatory proteins (IRPs) 1 and 2 [5, 179, 195].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [195]
In the citing paper
“Taken together, these data support that FPN expression is tightly controlled at both transcriptional and/or the translational levels,8,68,69 which allow multiple and diverse physiological effects to influence FPN activity at its various sites of expression.”
From RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation (2021) · cites this paper as [69]
In the citing paper
“Therefore, high levels of IRP2 are usually indicative of decreased cellular iron bioavailability.”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [48]
In the citing paper
“While IRP2 can mediate the degradation of ferritin and ferroportin mRNA [48], this must be insufficient to prevent their biosynthesis in the context of senescent cells.”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [48]
In the citing paper
“and stabilizes TfR1 mRNA (via binding to 3′ IRE) increasing its expression to up-regulate cellular iron uptake [48].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [48]
In the citing paper
“In this situation, IRP1 usually loses its iron-sulfur cluster and aconitase activity and binds IREs with high affinity [48], [50].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [48]
Citations
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BackgroundA Novel Mammalian Iron-regulated Protein Involved in Intracellular Iron Metabolism
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“In aconitases, a cubane iron-sulfur cluster is ligated by three cysteines within the enzymatic active site cleft, and the fourth iron of the cubane cluster binds substrat”
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Siderophore-Based Iron Acquisition and Pathogen Control
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Excited-state intramolecular proton-transfer (ESIPT) based fluorescence sensors and imaging agents
Sedgwick, A. C., Wu, L., Han, H., Bull, S. D., He, X., James, T. D., Sessler, J. L., Tang, B. Z., Tian, H., & Yoon, J. (2018) · Chemical Society Reviews · doi:10.1039/c8cs00185e · Cited by 1,589
Metalloproteins and metal sensing
Waldron, K. J., Rutherford, J. C., Ford, D., & Robinson, N. J. (2009) · Nature · doi:10.1038/nature08300 · Cited by 1,269
Function and biogenesis of iron-sulphur proteins
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The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease
Fang, X., Ardehali, H., Min, J., & Wang, F. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-022-00735-4 · Cited by 1,109
Metadata
- Authors
- Rouault, T. A.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Rouault, Tracey A
- ORCID
- Rouault, Tracey A
- Venue
- Nature Chemical Biology
- Published
- 2006-07-18
- Volume
- 2
- Issue
- 8
- Pages
- 406-414
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- 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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