Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2: Implications for degradation of oxidized proteins
Open accessAbstract
The ability of iron to catalyze formation of reactive oxygen species significantly contributes to its toxicity in cells and animals. Iron uptake and distribution is regulated tightly in mammalian cells, in part by iron regulatory protein 2 (IRP2), a protein that is degraded efficiently by the proteasome in iron-replete cells. Here, we demonstrate that IRP2 is oxidized and ubiquitinated in cells before degradation. Moreover, iron-dependent oxidation converts IRP2 into a substrate for ubiquitination in vitro . A regulatory pathway is described in which excess iron is sensed by its ability to catalyze site-specific oxidations in IRP2, oxidized IRP2 is ubiquitinated, and ubiquitinated IRP2 subsequently is degraded by the proteasome. Selective targeting and removal of oxidatively modified proteins may contribute to the turnover of many proteins that are degraded by the proteasome.
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Ferritin mRNA induction was observed during DMSO- or hemin-induced differentiation of mouse Friend leukemia cells and hemin-mediated differentiation of K562 human chronic myelogenous leukemia cells.
“Ferritin mRNA induction was observed during DMSO-or hemin-induced differentiation of mouse Friend leukemia cells (FLC) and hemin-mediated differentiation of K562 human chronic myelogenous leukemia cells (17, 143, 194).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [143]
A far-upstream region is an important responsive element that activates ferritin transcription during erythroid differentiation.
“Conversely, a far-upstream region was shown to be the important responsive element that activates ferritin transcription during erythroid differentiation (20, 143).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [143]
Nrf2 binds and activates the human ferritin H ARE.
“Nrf2 was shown to bind and activate the human ferritin H ARE (143, 301).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [143]
In human ferritin H transcription in K562 erythroid cells, hemin activates ferritin H ARE by recruiting activators such as JunD and Nrf2.
“In the case of human ferritin H transcription in K562 erythroid cells, hemin activates ferritin H ARE by recruiting several activators, such as JunD and Nrf2 (143).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [143]
The hemin-responsive element in the ferritin promoter region overlaps with the ARE of each human ferritin H and L gene.
“The hemin-responsive element in the ferritin promoter region was also shown to overlap with the ARE of each human ferritin H and L gene (133, 143).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [143]
Redox factor 1 is involved in ferritin ARE activation by Nrf2 during K562 differentiation.
“Moreover, redox factor 1, which was shown to enhance DNA binding of b-zip transcription factors through reduction of conserved cysteine residues (325), was involved in the ferritin ARE activation by Nrf2 during K562 differentiation (143).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [143]
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- Authors
- Iwai, K., Drake, S. K., Wehr, N. B., Weissman, A. M., LaVaute, T., Minato, N., Klausner, R. D., Levine, R. L., & Rouault, T. A.
- Affiliations
- Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-5430; Laboratory of Biochemistry, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892-0320; Laboratory of Immune Cell Biology, Division of Basic Sciences, National Cancer Institute, Bethesda, MD 20892; and Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606,...
- National Institutes of Health (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1998-04-28
- Volume
- 95
- Issue
- 9
- Pages
- 4924-4928
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC20189
- OpenAlex
- W2017107298
- Cited by
- 293
- References
- 27
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 7 · 2019: 5 · 2018: 4 · 2017: 4 · 2016: 3 · 2015: 5 · 2014: 7 · 2013: 7 · 2012: 12
- FWCI
- 14.13
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (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 › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- IRP2, protein oxidation, ubiquitination, proteasomal degradation, iron homeostasis, reactive oxygen species, iron toxicity, iron sensing
- MeSH terms
- Animals, Cell-Free System, Cysteine Endopeptidases, Iron, Iron-Sulfur Proteins, Multienzyme Complexes, Oxidation-Reduction, Recombinant Proteins, Ubiquitins, RNA-Binding Proteins, COS Cells, Iron-Regulatory Proteins, Iron Regulatory Protein 2, Proteasome Endopeptidase Complex
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