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

Peroxiredoxins are modulators of aging in yeast and multicellular organisms. The mechanisms by which peroxiredoxins stimulate H2O2 resistance and slow down aging are, however, unclear. Here we show that the yeast peroxiredoxin Tsa1 boosts H2O2 resistance and prevents aging independent of cellular H2O2 levels, but in a manner dependent on H2O2 signaling. More specifically, we pin-point a role of Tsa1 in repressing nutrient signaling via protein kinase A (PKA) that governs both H2O2 resistance and longevity. Tsa1 controls PKA activity at the level of the catalytic subunits and Tpk1 is redox-modified by Tsa1 on a conserved cysteine residue (Cys243) in Tpk1 upon H2O2 addition boosting cellular H2O2 resistance. Tpk1 redox modification dephosphorylates a conserved threonine 241 in the activation loop reducing enzyme activity. We discuss these results in the context of an integrative view on aging where nutrient signaling pathways constitute hubs integrating information from multiple aging-related conduits.