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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 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.

Pubmed ID: 19762596


  • Vashisht AA
  • Zumbrennen KB
  • Huang X
  • Powers DN
  • Durazo A
  • Sun D
  • Bhaskaran N
  • Persson A
  • Uhlen M
  • Sangfelt O
  • Spruck C
  • Leibold EA
  • Wohlschlegel JA


Science (New York, N.Y.)

Publication Data

October 30, 2009

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM45201
  • Agency: NIGMS NIH HHS, Id: R01 GM045201
  • Agency: NIGMS NIH HHS, Id: R01 GM045201-17
  • Agency: NIGMS NIH HHS, Id: R01 GM089778
  • Agency: NIGMS NIH HHS, Id: R01 GM089778-01A1

Mesh Terms

  • Cell Line
  • Cullin Proteins
  • F-Box Proteins
  • Hemerythrin
  • Homeostasis
  • Humans
  • Iron
  • Iron Regulatory Protein 1
  • Iron Regulatory Protein 2
  • Oxygen
  • Protein Structure, Tertiary
  • Recombinant Proteins
  • SKP Cullin F-Box Protein Ligases
  • Ubiquitin-Protein Ligases