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Molecular and Cellular Biology, January 2004, p. 330-337, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.330-337.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

S-Nitrosylation of IRP2 Regulates Its Stability via the Ubiquitin-Proteasome Pathway

Sangwon Kim,1,2 Simon S. Wing,2,3 and Prem Ponka1,2,4*

Lady Davis Institute for Medical Research, Jewish General Hospital,1 Departments of Medicine,2 Physiology,4 Polypeptide Hormone Laboratory, McGill University, Montreal, Quebec H3T 1E2, Canada3

Received 30 May 2003/ Returned for modification 21 July 2003/ Accepted 24 September 2003

Nitric oxide (NO) is an important signaling molecule that interacts with different targets depending on its redox state. NO can interact with thiol groups resulting in S-nitrosylation of proteins, but the functional implications of this modification are not yet fully understood. We have reported that treatment of RAW 264.7 cells with NO caused a decrease in levels of iron regulatory protein 2 (IRP2), which binds to iron-responsive elements present in untranslated regions of mRNAs for several proteins involved in iron metabolism. In this study, we show that NO causes S-nitrosylation of IRP2, both in vitro and in vivo, and this modification leads to IRP2 ubiquitination followed by its degradation in the proteasome. Moreover, mutation of one cysteine (C178S) prevents NO-mediated degradation of IRP2. Hence, S-nitrosylation is a novel signal for IRP2 degradation via the ubiquitin-proteasome pathway.

* Corresponding author. Mailing address: Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Ste-Catherine Rd., Montreal, QC H3T 1E2, Canada. Phone: (514) 340-8260. Fax: (514) 340-7502. E-mail: prem.ponka{at}mcgill.ca.

Molecular and Cellular Biology, January 2004, p. 330-337, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.330-337.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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