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Control of iron homeostasis by an iron-regulated ubiquitin ligase.

ABSTRACT: 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.

SUBMITTER: Vashisht AA

PROVIDER: S-EPMC2929180 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Control of iron homeostasis by an iron-regulated ubiquitin ligase.

Vashisht Ajay A AA Zumbrennen Kimberly B KB Huang Xinhua X Powers David N DN Durazo Armando A Sun Dahui D Bhaskaran Nimesh N Persson Anja A Uhlen Mathias M Sangfelt Olle O Spruck Charles C Leibold Elizabeth A EA Wohlschlegel James A JA

Science (New York, N.Y.) 20090917 5953

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 su ...[more]

PMID: 19762596

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