Iron-Dependent Oxidation, Ubiquitination, and Degradation of Iron Regulatory Protein 2: Implications for Degradation of Oxidized Proteins

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 protea...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1998-04, Vol.95 (9), p.4924-4928
Main Authors: Iwai, Kazuhiro, Drake, Steven K., Wehr, Nancy B., Weissman, Allan M., LaVaute, Timothy, Minato, Nagahiro, Klausner, Richard D., Levine, Rodney L., Rouault, Tracey A.
Format: Article
Language:English
Subjects:
Animals
Antibodies
Biochemistry
Biodegradation
Biological Sciences
Catalysts
Cell-Free System
Cells
COS Cells
Cysteine Endopeptidases - metabolism
Iron
Iron - metabolism
Iron Regulatory Protein 2
Iron regulatory proteins
Iron-Sulfur Proteins - metabolism
Lead
Multienzyme Complexes - metabolism
Oxidation
Oxidation-Reduction
Proteasome Endopeptidase Complex
Proteins
Recombinant Proteins - metabolism
RNA-Binding Proteins - metabolism
Ubiquitins
Ubiquitins - metabolism
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.95.9.4924