Control of Iron Homeostasis by an Iron-Regulated Ubiquitin Ligase

Eukaryotic cells require iron for survival and have developed regulatory mechanisms for maintaining appropriate intracellular iron concentrations. The degradation of iron regulatory protein 2 (IRP2) in iron-replete cells is a key event in this pathway, but the E3 ubiquitin ligase responsible for its...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2009-10, Vol.326 (5953), p.718-721
Main Authors: Vashisht, Ajay A, Zumbrennen, Kimberly B, Huang, Xinhua, Powers, David N, Durazo, Armando, Sun, Dahui, Bhaskaran, Nimesh, Persson, Anja, Uhlen, Mathias, Sangfelt, Olle, Spruck, Charles, Leibold, Elizabeth A, Wohlschlegel, James A
Format: Article
Language:English
Subjects:
Antibodies
Biochemistry
Biological and medical sciences
Cell Line
Cell physiology
Cellular biology
Cullin Proteins - metabolism
degradation
element-binding protein
F-Box Proteins - metabolism
Fundamental and applied biological sciences. Psychology
Half lives
HEK293 cells
Hemerythrin - metabolism
Homeostasis
Humans
Hypoxia
Iron
Iron - metabolism
Iron Regulatory Protein 1 - metabolism
Iron Regulatory Protein 2 - metabolism
Iron regulatory proteins
irp2
Medicin och hälsovetenskap
Miscellaneous
Molecular and cellular biology
Oxygen
Oxygen - metabolism
pathway
proteasome
protein identification technology
Protein Structure, Tertiary
Proteins
Recombinant Proteins - metabolism
Signal transduction
SKP Cullin F-Box Protein Ligases - metabolism
Small interfering RNA
Ubiquitin-Protein Ligase Complexes
Ubiquitin-Protein Ligases - metabolism
Ubiquitins
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Summary:Eukaryotic cells require iron for survival and have developed regulatory mechanisms for maintaining appropriate intracellular iron concentrations. The degradation of iron regulatory protein 2 (IRP2) in iron-replete cells is a key event in this pathway, but the E3 ubiquitin ligase responsible for its proteolysis has remained elusive. We found that a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus. Thus, iron homeostasis is regulated by a proteolytic pathway that couples IRP2 degradation to intracellular iron levels through the stability and activity of FBXL5.
ISSN:0036-8075
1095-9203
1095-9203
DOI:10.1126/science.1176333