Les peroxydases à thiol, relais dans la signalisation cellulaire redox associée au peroxyde d’hydrogène : mécanismes moléculaires responsables de la spécificité de l’activation du facteur de transcription Yap1 chez Saccharomyces cerevisiae

Abstract : Thiol-peroxidases play a central role in the physiology of hydrogen peroxide, an oxidant which can act as a cellular messenger. They catalyze H2O2 reduction by the very efficient reaction of a catalytic Cys residue, responsible for their ability to act as an H2O2 sensor and relay. In Saccharomyces cerevisiae, the H2O2-activation of the transcription factor Yap1, a key regulator of oxidative stress response, depends on the formation of intramolecular disulfide bonds catalyzed by the thiol peroxidase Orp1, through the reaction of the sulfenic acid intermediate with a Cys of Yap1 to form a mixed disulfide complex. Due to the high reactivity of the sulfenic acid species, several reactions can compete with Yap1. The study of the mechanisms underlying the specificity of the reaction between Orp1 and Yap1, and of the role of the Ybp1 protein as an essential partner of Yap1 activation, is the central question of this work. Our results show that Ybp1 can recruit Yap1 and Orp1 within a ternary complex that allows (i) strong activation of the reaction between the two partners and (ii) inhibition of the competition raised by the formation of an intramolecular disulfide bond within Orp1. The specificity of the activation of Yap1 by H2O2 therefore relies on mechanisms that combine intrinsic chemical reactivity of the sulfenic acid species and molecular recognition between Yap1, Orp1 and Ybp1, which would act as a scaffold. These principles, which afford rapid and specific activation of antioxidant defenses in Saccharomyces cerevisiae, could apply to other redox signaling pathways dependent on thiol peroxidase as a H2O2 sensor
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Antoine Bersweiler. Les peroxydases à thiol, relais dans la signalisation cellulaire redox associée au peroxyde d’hydrogène : mécanismes moléculaires responsables de la spécificité de l’activation du facteur de transcription Yap1 chez Saccharomyces cerevisiae. Biochimie, Biologie Moléculaire. Université de Lorraine, 2015. Français. ⟨NNT : 2015LORR0270⟩. ⟨tel-01754563⟩

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