Peroxiredoxin promotes longevity and H₂O₂-resistance in yeast through redox-modulation of protein kinase A

Peroxiredoxins are H₂O₂ scavenging enzymes that also carry out 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.