Identification of the ubiquitin–protein ligase that recognizes oxidized IRP2
Abstract
The ubiquitin system is involved in several basic cellular functions. Ubiquitination is carried out by a cascade of three reactions catalysed by the E1, E2 and E3 enzymes. Among these, the E3 ubiquitin-protein ligases have a pivotal role in determining the specificity of the system by recognizing the target substrates through defined targeting motifs. Although RING finger proteins constitute an important family of E3 ligases, only a few post-transcriptional modifications, including phosphorylation, proline hydroxylation and glycosylation, are known to function as recognition signals for E3. Iron regulatory protein 2 (IRP2), a modulator of iron metabolism, is regulated by iron-induced ubiquitination and degradation. Here we show that the RING finger protein HOIL-1 functions as an E3 ligase for oxidized IRP2, suggesting that oxidation is a specific recognition signal for ubiquitination. The oxidation of IRP2 is generated by haem, which binds to IRP2 in iron-rich cells, and by oxygen, indicating that the iron sensing of IRP2 depends on the synthesis and availability of haem.
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Several studies have observed colocalization of oxidative-damage indicators with regions of iron accumulation.
“Several studies have observed colocalization of such oxidative-damage indicators with regions of iron accumulation (334).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [334]
Markers of oxidative stress, including lipid and protein oxidation, have been observed in PD and AD.
“Befitting a model of altered iron-mediated mechanisms of damage in neurodegeneration, markers of oxidative stress, including lipid and protein oxidation, have been observed in PD and AD (334).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [334]
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Nitric Oxide Inhibits the Degradation of IRP2
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- Authors
- Yamanaka, K., Ishikawa, H., Megumi, Y., Tokunaga, F., Kanie, M., Rouault, T. A., Morishima, I., Minato, N., Ishimori, K., & Iwai, K.
- Affiliations
- Kyoto University (JP)
- Osaka City University (JP)
- National Institutes of Health (US)
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2003-03-10
- Volume
- 5
- Issue
- 4
- Pages
- 336-340
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W1998851985
- Semantic Scholar
- f146b70856c534a923f91ed4c4d79cdc9669e84b
- Cited by
- 181
- References
- 25
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 7 · 2019: 8 · 2018: 5 · 2017: 2 · 2016: 3 · 2015: 5 · 2014: 9 · 2013: 4 · 2012: 25
- FWCI
- 5.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- IRP2, E3 ubiquitin ligase, RING finger protein, HOIL-1, ubiquitination, heme, iron sensing, protein degradation, iron metabolism
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Cloning, Molecular, Eukaryotic Cells, Genetic Vectors, Heme, Humans, Iron, Ligases, Molecular Sequence Data, Mutation, Oxidation-Reduction, Transcription Factors, Gene Expression Regulation, Enzymologic, COS Cells, Ubiquitin, Iron Regulatory Protein 2, Ubiquitin-Protein Ligases
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