title: Negative feedback regulation of the yeast CTH1 and CTH2 mRNA binding proteins is required for adaptation to iron deficiency and iron supplementation.
abstract: Iron (Fe) is an essential element for all eukaryotic organisms because it functions as a cofactor in a wide range of biochemical processes. Cells have developed sophisticated mechanisms to tightly control Fe utilization in response to alterations in cellular demands and bioavailability. In response to Fe deficiency, the yeast Saccharomyces cerevisiae activates transcription of the CTH1 and CTH2 genes, which encode proteins that bind to AU-rich elements (AREs) within the 3' untranslated regions (3'UTRs) of many mRNAs, leading to metabolic reprogramming of Fe-dependent pathways and decreased Fe storage. The precise mechanisms underlying Cth1 and Cth2 function and regulation are incompletely understood. We report here that the Cth1 and Cth2 proteins specifically bind in vivo to AREs located at the 3'UTRs of their own transcripts in an auto- and cross-regulated mechanism that limits their expression. By mutagenesis of the AREs within the CTH2 transcript, we demonstrate that a Cth2 negative-feedback loop is required for the efficient decline in Cth2 protein levels observed upon a rapid rise in Fe availability. Importantly, Cth2 autoregulation is critical for the appropriate recovery of Fe-dependent processes and resumption of growth in response to a change from Fe deficiency to Fe supplementation.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Mar
authors.initials: M
authors.lastname: Martínez-Pastor
authors.forename: Sandra V
authors.initials: SV
authors.lastname: Vergara
authors.forename: Sergi
authors.initials: S
authors.lastname: Puig
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Thiele
mesh_terms: D020413:3' Untranslated Regions; D063307:AU Rich Elements; D000222:Adaptation, Physiological; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C102098:CTH1 protein, S cerevisiae; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; C091790:TIS11 protein, S cerevisiae; D014157:Transcription Factors; D051816:Tristetraprolin; D007501:Iron