title: Two redox centers within Yap1 for H2O2 and thiol-reactive chemicals signaling.
abstract: The Yap1 transcription factor regulates yeast responses to H2O2 and to several unrelated chemicals and metals. Activation by H2O2 involves Yap1 Cys303-Cys598 intra-molecular disulfide bond formation directed by the H2O2 sensor Orp1/Gpx3. We show here that the electrophile N-ethylmaleimide activates Yap1 by covalent modification of Yap1 C-terminal Cys598, Cys620, and Cys629, in an Orp1 and Yap1-oxidation-independent way, thus establishing an alternate and distinct mode of Yap1 activation. We also show that menadione, a superoxide anion generator and a highly reactive electrophile, operates both modes of Yap1 activation. Further, the Yap1 C-terminal domain reactivity towards other electrophiles (4-hydroxynonenal, iodoacetamide) and metals (cadmium, selenium) suggests a common mechanism for sensing thiol reactive chemicals, involving thiol chemical modification. We propose that Yap1 has two distinct molecular redox centers, one triggered by ROS (hydroperoxides and the superoxide anion) and the other by chemicals with thiol reactivity (electrophiles and divalent heavy metals cations). These data indicate that yeast cells cannot sense these compounds through the same molecular devices, albeit they are all electrophilic.
authors.affiliation: Laboratoire Stress Oxydants et Cancers, Service de Biochimie et de Génétique Moléculaire, Département de Biologie Joliot Curie, CEA-Saclay, Gif-sur-Yvette, France.
authors.forename: Dulce
authors.initials: D
authors.lastname: Azevedo
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tacnet
authors.forename: Agnès
authors.initials: A
authors.lastname: Delaunay
authors.forename: Claudina
authors.initials: C
authors.lastname: Rodrigues-Pousada
authors.forename: Michel B
authors.initials: MB
authors.lastname: Toledano
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D002104:Cadmium / Q000494:pharmacology; D004220:Disulfides / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology*; D007460:Iodoacetamide / Q000494:pharmacology; D013058:Mass Spectrometry; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction; D012331:RNA, Fungal / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D012643:Selenium / Q000494:pharmacology; D015398:Signal Transduction; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: D000447:Aldehydes; D000933:Antifibrinolytic Agents; D004220:Disulfides; D004791:Enzyme Inhibitors; D016877:Oxidants; D012331:RNA, Fungal; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D013438:Sulfhydryl Compounds; D014157:Transcription Factors; C086677:YAP1 protein, S cerevisiae; D002104:Cadmium; D013481:Superoxides; D024483:Vitamin K 3; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D012643:Selenium; C027576:4-hydroxy-2-nonenal; D007460:Iodoacetamide