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Molecular and Cellular Biology, April 2007, p. 2423-2430, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01111-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Iron-Dependent Degradation of Apo-IRP1 by the Ubiquitin-Proteasome Pathway{triangledown}

Jian Wang ,1,¶,{dagger} Carine Fillebeen,1,{dagger} Guohua Chen,1,# Annette Biederbick,2 Roland Lill,2 and Kostas Pantopoulos1,3*

Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote-Ste-Catherine Road, Montreal, Quebec H3T 1E2, Canada,1 Institut für Zytobiologie, Philipps Universität Marburg, Robert Koch Str. 6, 35037 Marburg, Germany,2 Department of Medicine, McGill University, Montreal, Quebec, Canada3

Received 20 June 2006/ Returned for modification 1 August 2006/ Accepted 12 January 2007

Iron regulatory protein 1 (IRP1) controls the translation or stability of several mRNAs by binding to "iron-responsive elements" within their untranslated regions. In iron-replete cells, IRP1 assembles a cubane iron-sulfur cluster (ISC) that inhibits RNA-binding activity and converts the protein to cytosolic aconitase. We show that the constitutive IRP1C437S mutant, which fails to form an ISC, is destabilized by iron. Thus, exposure of H1299 cells to ferric ammonium citrate reduced the half-life of transfected IRP1C437S from ~24 h to ~10 h. The iron-dependent degradation of IRP1C437S involved ubiquitination, required ongoing transcription and translation, and could be efficiently blocked by the proteasomal inhibitors MG132 and lactacystin. Similar results were obtained with overexpressed wild-type IRP1, which predominated in the apo-form even in iron-loaded H1299 cells, possibly due to saturation of the ISC assembly machinery. Importantly, inhibition of ISC biogenesis in HeLa cells by small interfering RNA knockdown of the cysteine desulfurase Nfs1 sensitized endogenous IRP1 for iron-dependent degradation. Collectively, these data uncover a mechanism for the regulation of IRP1 abundance as a means to control its RNA-binding activity, when the ISC assembly pathway is impaired.

* Corresponding author. Mailing address: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote-Ste-Catherine Road, Montreal, Quebec H3T 1E2, Canada. Phone: (514) 340-8260, ext. 5293. Fax: (514) 340-7502. E-mail: kostas.pantopoulos{at}mcgill.ca.

{triangledown} Published ahead of print on 22 January 2007.

Present address: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX.

{dagger} These authors equally contributed to the work.

# Present address: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX.

Molecular and Cellular Biology, April 2007, p. 2423-2430, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01111-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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