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

2020; eLife Sciences Publications Ltd; Volume: 9; Linguagem: Inglês

10.7554/elife.60346

2050-084X

Friederike Roger, Cecilia Picazo, Wolfgang Reiter, Marouane Libiad, Chikako Asami, Sarah Hanzén, Chunxia Gao, Gilles Lagniel, Niek Welkenhuysen, Jean Labarre, Thomas Nyström, Morten Grøtli, Markus Hartl, Michel B. Tolédano, Mikael Molin,

Fungal and yeast genetics research

Peroxiredoxins are H 2 O 2 scavenging enzymes that also carry out H 2 O 2 signaling and chaperone functions. In yeast, the major cytosolic peroxiredoxin, Tsa1 is required for both promoting resistance to H 2 O 2 and extending lifespan upon caloric restriction. We show here that Tsa1 effects both these functions not by scavenging H 2 O 2 , 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 H 2 O 2 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 H 2 O 2 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 H 2 O 2 .