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Science 326 (5953): 718-721

Copyright © 2009 by the American Association for the Advancement of Science

Control of Iron Homeostasis by an Iron-Regulated Ubiquitin Ligase

Ajay A. Vashisht,1 Kimberly B. Zumbrennen,2 Xinhua Huang,1 David N. Powers,1 Armando Durazo,3 Dahui Sun,4 Nimesh Bhaskaran,5 Anja Persson,6 Mathias Uhlen,6 Olle Sangfelt,5 Charles Spruck,4 Elizabeth A. Leibold,2 James A. Wohlschlegel1,*

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.

1 Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
2 Departments of Medicine and Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
3 Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA.
4 Sidney Kimmel Cancer Center, San Diego, CA 92121, USA.
5 Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Hospital, SE-171 76 Stockholm, Sweden.
6 School of Biotechnology, Department of Proteomics, Royal Institute of Technology/AlbaNova, SE-106 91 Stockholm, Sweden.

* To whom correspondence should be addressed. E-mail: jwohl{at}mednet.ucla.edu

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