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Control of Iron Homeostasis by an Iron-Regulated Ubiquitin Ligase

Science, 30 October 2009
Vol. 326, Issue 5953, p. 718-721
DOI: 10.1126/science.1176333

Control of Iron Homeostasis by an Iron-Regulated Ubiquitin Ligase

  1. Ajay A. Vashisht1,
  2. Kimberly B. Zumbrennen2,
  3. Xinhua Huang1,
  4. David N. Powers1,
  5. Armando Durazo3,
  6. Dahui Sun4,
  7. Nimesh Bhaskaran5,
  8. Anja Persson6,
  9. Mathias Uhlen6,
  10. Olle Sangfelt5,
  11. Charles Spruck4,
  12. Elizabeth A. Leibold2,
  13. James A. Wohlschlegel1,*
  1. 1Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
  2. 2Departments of Medicine and Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
  3. 3Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA.
  4. 4Sidney Kimmel Cancer Center, San Diego, CA 92121, USA.
  5. 5Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Hospital, SE-171 76 Stockholm, Sweden.
  6. 6School of Biotechnology, Department of Proteomics, Royal Institute of Technology/AlbaNova, SE-106 91 Stockholm, Sweden.
  1. *To whom correspondence should be addressed. E-mail: jwohl{at}mednet.ucla.edu

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.

  • Received for publication 15 May 2009.
  • Accepted for publication 14 August 2009.

Citation:

A. A. Vashisht, K. B. Zumbrennen, X. Huang, D. N. Powers, A. Durazo, D. Sun, N. Bhaskaran, A. Persson, M. Uhlen, O. Sangfelt, C. Spruck, E. A. Leibold, and J. A. Wohlschlegel, Control of Iron Homeostasis by an Iron-Regulated Ubiquitin Ligase. Science 326, 718-721 (2009).

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