Peroxiredoxins are H2O2 scavenging enzymes that also carry H2O2 signaling and chaperone functions. In yeast, the major cytosolic peroxiredoxin, Tsa1 is required for both promoting resistance to H2O2 and extending lifespan upon caloric restriction. We show here that Tsa1 effects both these functions not by scavenging H2O2, but by repressing the nutrient signaling Ras-cAMP-PKA pathway at the level of the protein kinase A (PKA) enzyme. Tsa1 stimulates sulfenylation of cysteines in the PKA catalytic subunit by H2O2 and a significant proportion of the catalytic subunits are glutathionylated on two cysteine residues. Redox modification of the conserved Cys243 inhibits the phosphorylation of a conserved Thr241 in the kinase activation loop and enzyme activity, and preventing Thr241 phosphorylation can overcome the H2O2 sensitivity of Tsa1-deficient cells. Results support a model of aging where nutrient signaling pathways constitute hubs integrating information from multiple aging-related conduits, including a peroxiredoxin-dependent response to H2O2.
1Peroxiredoxins are major peroxide scavenging enzymes and mediators of the beneficial effects of 2 caloric restriction on aging. By which mechanism peroxiredoxins stimulate H2O2 resistance and slow 3 down aging is, however, incompletely understood. Here we show that the yeast peroxiredoxin Tsa1 4boosts H2O2 tolerance and delays aging not by its action of scavenging H2O2, but by repressing the 5 nutrient signaling protein kinase A (PKA). Tsa1 represses PKA activity through redox modification of 6 the catalytic subunits and a significant proportion of catalytic subunits are glutathionylated on two 7 cysteine residues. Redox modification of the conserved Cys243 in the catalytic subunits inhibits the 8 phosphorylation of a conserved Thr241 in the kinase activation loop and enzyme activity and 9preventing Thr241 phosphorylation can overcome the H2O2 sensitivity of Tsa1-deficient cells. Results 10 support a model of aging where nutrient signaling pathways constitute hubs integrating information 11 from multiple aging-related conduits including a peroxiredoxin-dependent responding to H2O2.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.