title: Repression of the Low Affinity Iron Transporter Gene FET4: A NOVEL MECHANISM AGAINST CADMIUM TOXICITY ORCHESTRATED BY YAP1 VIA ROX1.
abstract: Cadmium is a well known mutagenic metal that can enter cells via nonspecific metal transporters, causing several cellular damages and eventually leading to death. In the yeast Saccharomyces cerevisiae, the transcription factor Yap1 plays a key role in the regulation of several genes involved in metal stress response. We have previously shown that Yap1 represses the expression of FET4, a gene encoding a low affinity iron transporter able to transport metals other than iron. Here, we have studied the relevance of this repression in cell tolerance to cadmium. Our results indicate that genomic deletion of Yap1 increases FET4 transcript and protein levels. In addition, the cadmium toxicity exhibited by this strain is completely reversed by co-deletion of FET4 gene. These data correlate well with the increased intracellular levels of cadmium observed in the mutant yap1. Rox1, a well known aerobic repressor of hypoxic genes, conveys the Yap1-mediated repression of FET4. We further show that, in a scenario where the activity of Yap1 or Rox1 is compromised, cells activate post-transcriptional mechanisms, involving the exoribonuclease Xrn1, to compensate the derepression of FET4. Our data thus reveal a novel protection mechanism against cadmium toxicity mediated by Yap1 that relies on the aerobic repression of FET4 and results in the impairment of cadmium uptake.
authors.affiliation: From the Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa and.
authors.forename: Soraia M
authors.initials: SM
authors.lastname: Caetano
authors.affiliation: From the Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa and the Instituto de Biologia Experimental e Tecnológica, 2781-901 Oeiras, Portugal.
authors.forename: Regina
authors.identifier: http://orcid.org/0000-0003-0552-8480
authors.initials: R
authors.lastname: Menezes
authors.affiliation: From the Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa and.
authors.forename: Catarina
authors.identifier: http://orcid.org/0000-0002-9442-2225
authors.initials: C
authors.lastname: Amaral
authors.affiliation: From the Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa and pimentel@itqb.unl.pt claudina@itqb.unl.pt.
authors.forename: Claudina
authors.identifier: http://orcid.org/0000-0002-5075-3639
authors.initials: C
authors.lastname: Rodrigues-Pousada
authors.affiliation: From the Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa and pimentel@itqb.unl.pt claudina@itqb.unl.pt.
authors.forename: Catarina
authors.identifier: http://orcid.org/0000-0002-5158-6414
authors.initials: C
authors.lastname: Pimentel
mesh_terms: D001692:Biological Transport / Q000235:genetics; D002104:Cadmium / Q000378:metabolism* / Q000633:toxicity; D027682:Cation Transport Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000079922:Copper Transport Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005095:Exoribonucleases / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; D004268:DNA-Binding Proteins; C105847:FET4 protein, S cerevisiae; D033862:Iron-Binding Proteins; C083348:ROX1 protein, S cerevisiae; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C086677:YAP1 protein, S cerevisiae; D002104:Cadmium; D007501:Iron; D005095:Exoribonucleases; C068398:XRN1 protein, S cerevisiae
keywords: Fet4; Rox1; Yap1; cadmium; gene regulation; iron; metal; stress response; yeast metabolism