Mass Spectrometry Facility, Department of Biochemistry, Max F. Perutz Laboratories, University of Vienna, Vienna BioCenter, Vienna, Austria
Marouane Libiad
Oxidative Stress and Cancer Laboratory, Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif sur Yvette, France
Chikako Asami
Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
Sarah Hanzén
Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
Chunxia Gao
Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
Gilles Lagniel
Oxidative Stress and Cancer Laboratory, Integrative Biology and Molecular Genetics Unit (SBIGEM), CEA Saclay, France
Niek Welkenhuysen
Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden
Jean Labarre
Oxidative Stress and Cancer Laboratory, Integrative Biology and Molecular Genetics Unit (SBIGEM), CEA Saclay, France
Oxidative Stress and Cancer Laboratory, Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif sur Yvette, France
Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden; Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
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.
