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J. Biol. Chem., Vol. 281, Issue 26, 17661-17669, June 30, 2006

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Role of Glutaredoxin-3 and Glutaredoxin-4 in the Iron Regulation of the Aft1 Transcriptional Activator in Saccharomyces cerevisiae^*

Luis Ojeda, Greg Keller, Ulrich Muhlenhoff, Julian C. Rutherford, Roland Lill, and Dennis R. Winge¹

From the University of Utah Health Sciences Center, Departments of Medicine and Biochemistry, Salt Lake City, Utah 84132 and Institut fur Zytobiologie und Zytopathologie Philipps-Universitat Marburg, Robert-Koch-Strasse 6, 35033 Marburg, Germany

The transcription factors Aft1 and Aft2 from Saccharomyces cerevisiae regulate the expression of genes involved in iron homeostasis. These factors induce the expression of iron regulon genes in iron-deficient yeast but are inactivated in iron-replete cells. Iron inhibition of Aft1/Aft2 was previously shown to be dependent on mitochondrial components required for cytosolic iron sulfur protein biogenesis. We presently show that the nuclear monothiol glutaredoxins Grx3 and Grx4 are critical for iron inhibition of Aft1 in yeast cells. Cells lacking both glutaredoxins show constitutive expression of iron regulon genes. Overexpression of Grx4 attenuates wild type Aft1 activity. The thioredoxin-like domain in Grx3 and Grx4 is dispensable in mediating iron inhibition of Aft1 activity, whereas the conserved cysteine that is part of the conserved CGFS motif in monothiol glutaredoxins is essential for this function. Grx3 and Grx4 interact with Aft1 as shown by two-hybrid interactions and co-immunoprecipitation assays. The interaction between glutaredoxins and Aft1 is not modulated by the iron status of cells but is dependent on the conserved glutaredoxin domain Cys residue. Thus, Grx3 and Grx4 are novel components required for Aft1 iron regulation that most likely occurs in the nucleus.

Received for publication, March 7, 2006 , and in revised form, April 24, 2006.

^* This work was supported by National Institutes of Health Grant CA61286 (to D. R. W.) and grants of the Sonderforschungsbereich 593, Deutsche Forschungsgemeinschaft (Gottfried Wilhelm Leibniz program), Fonds der chemischen Industrie, and the European Commission (to R. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 801-585-5103; Fax: 801-585-5469; E-mail: dennis.winge{at}hsc.utah.edu.

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