Requirements for iron-regulated degradation of the RNA binding protein, iron regulatory protein 2
Open accessAbstract
Iron regulatory proteins (IRPs) regulate the expression of genes involved in iron metabolism whose transcripts contain RNA stem-loop motifs known as iron-responsive elements (IREs). When iron concentrations are low, IRPs bind to IREs in the 5' untranslated region (UTR) of transcripts where they repress translation, or the 3' UTR of transcripts where they inhibit degradation. The RNA binding activities of the homologous proteins IRP1 and IRP2 are both regulated post-translationally. The binding activity of IRP2 is regulated by the degradation of the protein when cells are iron-replete. Here, we demonstrate that a 73 amino acid sequence that corresponds to a unique exon in IRP2 contains a sequence required for rapid degradation in iron-replete cells. The deletion of this sequence eliminates the rapid turnover of IRP2, whereas the transfer of this sequence to the corresponding position in the homologous protein IRP1 confers the capacity for iron-dependent degradation upon IRP1. Site-directed mutagenesis has demonstrated that specific cysteines within the IRP2 exon are required for iron-dependent degradation. The degradation of IRP2 appears to be mediated by the proteasome in iron-replete cells. When degradation is prevented, the RNA binding activity of IRP2 is not regulated by iron concentration. Thus, degradation is required for the regulation of the RNA binding activity of IRP2.
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High levels of IRP2 are usually indicative of decreased cellular iron bioavailability.
“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 [52]
Individuals with iron-overload disorders such as HH or β-thalassemia may have plasma NTBI in the micromolar range.
“Individuals with iron-overload disorders such as HH or β-thalassemia may have plasma NTBI in the micromolar range (144).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [144]
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- Authors
- Iwai, K., Klausner, R. D., & Rouault, T. A.
- Affiliations
- National Institutes of Health (US)
- ORCID
- Rouault, T. A.
- Venue
- The EMBO Journal
- Published
- 1995-11-01
- Volume
- 14
- Issue
- 21
- Pages
- 5350-5357
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC394644
- OpenAlex
- W153290133
- Cited by
- 211
- References
- 35
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 4 · 2018: 7 · 2017: 5 · 2016: 2 · 2015: 5 · 2014: 3 · 2013: 1 · 2012: 3
- FWCI
- 7.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- IRP2, iron regulatory protein 1, iron-responsive element, iron metabolism, proteasome, cysteine residues, exon deletion, post-translational regulation, translation repression
- MeSH terms
- Amino Acid Sequence, Cysteine, Exons, Humans, Iron, Molecular Sequence Data, Protein Processing, Post-Translational, Tumor Cells, Cultured, Mutagenesis, Site-Directed, RNA-Binding Proteins, Gene Deletion, Sequence Analysis, Iron-Regulatory Proteins, Iron Regulatory Protein 1, Iron Regulatory Protein 2
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