title: Activation of the iron regulon by the yeast Aft1/Aft2 transcription factors depends on mitochondrial but not cytosolic iron-sulfur protein biogenesis.
abstract: Two transcriptional activators, Aft1 and Aft2, regulate iron homeostasis in Saccharomyces cerevisiae. 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 is abrogated in cells defective for Fe-S cluster biogenesis within the mitochondrial matrix (Chen, O. S., Crisp, R. J., Valachovic, M., Bard, M., Winge, D. R., and Kaplan, J. (2004) J. Biol. Chem. 279, 29513-29518). To determine whether iron sensing by Aft1/Aft2 requires the function of the mitochondrial Fe-S export and cytosolic Fe-S protein assembly systems, we evaluated the expression of the iron regulon in cells depleted of glutathione and in cells depleted of Atm1, Nar1, Cfd1, and Nbp35. The iron regulon is induced in cells depleted of Atm1 with Aft1 largely responsible for the induced gene expression. Aft2 is activated at a later time in Atm1-depleted cells. Likewise, the iron regulon is induced in cells depleted of glutathione. In contrast, repression of NAR1, CFD1, or NBP35 fails to induce the iron regulon despite strong inhibition of cytosolic/nuclear Fe-S protein assembly. Thus, iron sensing by Aft1/Aft2 is not linked to the maturation of cytosolic/nuclear Fe-S proteins, but the mitochondrial inner membrane transporter Atm1 is important to transport the inhibitory signal. Although Aft1 and Aft2 sense a signal emanating from the Fe-S cluster biogenesis pathway, there is no indication that the proteins are inhibited by direct binding of an Fe-S cluster.
authors.affiliation: University of Utah Health Sciences Center, Department of Medicine, Salt Lake City, Utah 84132, USA.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Rutherford
authors.forename: Luis
authors.initials: L
authors.lastname: Ojeda
authors.forename: Janneke
authors.initials: J
authors.lastname: Balk
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mühlenhoff
authors.forename: Roland
authors.initials: R
authors.lastname: Lill
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Winge
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D004171:Diploidy; D005656:Fungal Proteins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D005978:Glutathione / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006720:Homozygote; D007501:Iron / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D018085:Regulon; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C090297:AFT1 protein, S cerevisiae; C436328:Aft2 protein, S cerevisiae; D005656:Fungal Proteins; D007506:Iron-Sulfur Proteins; C102265:NBP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D007501:Iron; D050862:Oxidoreductases Acting on Sulfur Group Donors; D000251:Adenosine Triphosphatases; D019204:GTP-Binding Proteins; D005978:Glutathione