title: Iron regulation through the back door: iron-dependent metabolite levels contribute to transcriptional adaptation to iron deprivation in Saccharomyces cerevisiae.
abstract: Budding yeast (Saccharomyces cerevisiae) responds to iron deprivation both by Aft1-Aft2-dependent transcriptional activation of genes involved in cellular iron uptake and by Cth1-Cth2-specific degradation of certain mRNAs coding for iron-dependent biosynthetic components. Here, we provide evidence for a novel principle of iron-responsive gene expression. This regulatory mechanism is based on the modulation of transcription through the iron-dependent variation of levels of regulatory metabolites. As an example, the LEU1 gene of branched-chain amino acid biosynthesis is downregulated under iron-limiting conditions through depletion of the metabolic intermediate alpha-isopropylmalate, which functions as a key transcriptional coactivator of the Leu3 transcription factor. Synthesis of alpha-isopropylmalate involves the iron-sulfur protein Ilv3, which is inactivated under iron deficiency. As another example, decreased mRNA levels of the cytochrome c-encoding CYC1 gene under iron-limiting conditions involve heme-dependent transcriptional regulation via the Hap1 transcription factor. Synthesis of the iron-containing heme is directly correlated with iron availability. Thus, the iron-responsive expression of genes that are downregulated under iron-limiting conditions is conferred by two independent regulatory mechanisms: transcriptional regulation through iron-responsive metabolites and posttranscriptional mRNA degradation. Only the combination of the two processes provides a quantitative description of the response to iron deprivation in yeast.
authors.affiliation: Institut für Zytobiologie und Zytopathologie, Philipps-Universität Marburg, Robert-Koch-Strasse 6, 35032 Marburg, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ihrig
authors.forename: Anja
authors.initials: A
authors.lastname: Hausmann
authors.forename: Anika
authors.initials: A
authors.lastname: Hain
authors.forename: Nadine
authors.initials: N
authors.lastname: Richter
authors.forename: Iqbal
authors.initials: I
authors.lastname: Hamza
authors.forename: Roland
authors.initials: R
authors.lastname: Lill
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mühlenhoff
mesh_terms: D050539:3-Isopropylmalate Dehydrogenase / Q000235:genetics; D023081:CCAAT-Binding Factor / Q000235:genetics; D002570:Ceruloplasmin / Q000235:genetics; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005294:Ferrochelatase / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D015966:Gene Expression Regulation, Fungal / Q000502:physiology*; D006418:Heme / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D006836:Hydro-Lyases / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D000090463:Iron Deficiencies; D007535:Isomerases / Q000235:genetics / Q000378:metabolism; D008293:Malates / Q000378:metabolism* / Q000494:pharmacology; D010544:Peroxidases / Q000235:genetics; D010618:Phenanthrolines / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013728:Terminator Regions, Genetic / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D051816:Tristetraprolin / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: C090297:AFT1 protein, S cerevisiae; D023081:CCAAT-Binding Factor; C102098:CTH1 protein, S cerevisiae; C014059:CYC1 protein, S cerevisiae; D004268:DNA-Binding Proteins; C058452:HAP1 protein, S cerevisiae; C061437:HAP4 protein, S cerevisiae; D007502:Iron Chelating Agents; C063667:LEU3 protein, S cerevisiae; D008293:Malates; D010618:Phenanthrolines; D029701:Saccharomyces cerevisiae Proteins; C091790:TIS11 protein, S cerevisiae; D015534:Trans-Activators; D014157:Transcription Factors; D051816:Tristetraprolin; C005906:alpha-isopropylmalate; D006418:Heme; C006686:bathophenanthroline; D045304:Cytochromes c; D007501:Iron; D050539:3-Isopropylmalate Dehydrogenase; C524993:LEU2 protein, S cerevisiae; C478774:HMX1 protein, S cerevisiae; D010544:Peroxidases; D002570:Ceruloplasmin; C085513:FET3 protein, S cerevisiae; D006836:Hydro-Lyases; C032241:isopropylmalate isomerase; C020052:dihydroxyacid dehydratase; D005294:Ferrochelatase; D007535:Isomerases