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 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.
Iwai
K
K
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-5430, USA.
Drake
S K
SK
Wehr
N B
NB
Weissman
A M
AM
LaVaute
T
T
Minato
N
N
Klausner
R D
RD
Levine
R L
RL
Rouault
T A
TA
D000818:Animals; D019556:COS Cells; D002474:Cell-Free System; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D035942:Iron Regulatory Protein 2; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism*; D010084:Oxidation-Reduction; D046988:Proteasome Endopeptidase Complex; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism
D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D009097:Multienzyme Complexes; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D014452:Ubiquitins; D007501:Iron; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D035942:Iron Regulatory Protein 2