title: Identification of FRA1 and FRA2 as genes involved in regulating the yeast iron regulon in response to decreased mitochondrial iron-sulfur cluster synthesis.
abstract: 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.
authors.affiliation: Department of Pathology and Departments of Biochemistry and Medicine, School of Medicine, University of Utah, Salt Lake City Utah 84132, USA.
authors.forename: Attila
authors.initials: A
authors.lastname: Kumánovics
authors.forename: Opal S
authors.initials: OS
authors.lastname: Chen
authors.forename: Liangtao
authors.initials: L
authors.lastname: Li
authors.forename: Dustin
authors.initials: D
authors.lastname: Bagley
authors.forename: Erika M
authors.initials: EM
authors.lastname: Adkins
authors.forename: Huilan
authors.initials: H
authors.lastname: Lin
authors.forename: Nin N
authors.initials: NN
authors.lastname: Dingra
authors.forename: Caryn E
authors.initials: CE
authors.lastname: Outten
authors.forename: Greg
authors.initials: G
authors.lastname: Keller
authors.forename: Dennis
authors.initials: D
authors.lastname: Winge
authors.forename: Diane M
authors.initials: DM
authors.lastname: Ward
authors.forename: Jerry
authors.initials: J
authors.lastname: Kaplan
mesh_terms: D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005656:Fungal Proteins / Q000737:chemistry*; D017353:Gene Deletion; D005816:Genetic Complementation Test; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000737:chemistry*; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C529265:FRA1 protein, S cerevisiae; C529266:FRA2 protein, S cerevisiae; D005656:Fungal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007506:Iron-Sulfur Proteins; D029701:Saccharomyces cerevisiae Proteins; D007501:Iron