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J. Biol. Chem., Vol. 283, Issue 16, 10276-10286, April 18, 2008

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Identification of FRA1 and FRA2 as Genes Involved in Regulating the Yeast Iron Regulon in Response to Decreased Mitochondrial Iron-Sulfur Cluster Synthesis^*

Attila Kumánovics¹, Opal S. Chen, Liangtao Li, Dustin Bagley, Erika M. Adkins, Huilan Lin, Nin N. Dingra, Caryn E. Outten, Greg Keller^¶, Dennis Winge^¶, Diane M. Ward, and Jerry Kaplan²

From the Department of Pathology and ^¶Departments of Biochemistry and Medicine, School of Medicine, University of Utah, Salt Lake City Utah 84132 and the Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208

The nature of the connection between mitochondrial Fe-S cluster synthesis and the iron-sensitive transcription factor Aft1 in regulating the expression of the iron transport system in Saccharomyces cerevisiae is not known. Using a genetic screen, we identified two novel cytosolic proteins, Fra1 and Fra2, that are part of a complex that interprets the signal derived from mitochondrial Fe-S synthesis. We found that mutations in FRA1 (YLL029W) and FRA2 (YGL220W) led to an increase in transcription of the iron regulon. In cells incubated in high iron medium, deletion of either FRA gene results in the translocation of the low iron-sensing transcription factor Aft1 into the nucleus, where it occupies the FET3 promoter. Deletion of either FRA gene has the same effect on transcription as deletion of both genes and is not additive with activation of the iron regulon due to loss of mitochondrial Fe-S cluster synthesis. These observations suggest that the FRA proteins are in the same signal transduction pathway as Fe-S cluster synthesis. We show that Fra1 and Fra2 interact in the cytosol in an iron-independent fashion. The Fra1-Fra2 complex binds to Grx3 and Grx4, two cytosolic monothiol glutaredoxins, in an iron-independent fashion. These results show that the Fra-Grx complex is an intermediate between the production of mitochondrial Fe-S clusters and transcription of the iron regulon.

Received for publication, February 12, 2008

^* This work was supported by National Institutes of Health (NIH) Grants DK30534 and DK52380 (to J. K.), GM083292 (to D. W.), and ES13780 (to C. O.). Support for use of the Core Facilities was provided through NCI, National Institutes of Health, Grant NCI-CCSG P30CA 42014 and NIDDK, NIH, Center of Excellence Award 5P30KD72437. 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 Supported by National Institutes of Health Training Grant T32 DK07115-29.

² To whom correspondence should be addressed. Tel.: 801-581-7427; E-mail: jerry.kaplan{at}path.utah.edu.

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