Abstract
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.
Highlights
Caloric restriction (CR) is an intervention that slows down aging and reduces the incidence of agerelated disease from the unicellular baker’s yeast (Lin et al, 2000) to rhesus monkeys (Mattison et al, 2017)
Deletion of PDE2 decreased the lifespan of the wild type strain by 45% (Figure 1B), as previously shown (Lin et al, 2000), and prevented the increased lifespan conferred by mild overexpression of TSA1, which indicates that protein kinase A (PKA) activity is dominant over Tsa1, and suggests that Tsa1 might slow down aging by decreasing PKA activity
Caloric restriction is established as a measure that extends the lifespan of organisms from yeast to primates and this effect occurs by reduced nutrient and/or growth signaling through the insulin/IGF1, TOR and protein kinase A pathways
Summary
Caloric restriction (CR) is an intervention that slows down aging and reduces the incidence of agerelated disease from the unicellular baker’s yeast (Lin et al, 2000) to rhesus monkeys (Mattison et al, 2017). Tsa1-dependent oxidation of the catalytic subunit reduced enzyme activity and increased H2O2 resistance in part through dephosphorylating a conserved threonine (Thr241) in the kinase activation loop. These results indicate that peroxiredoxins slow down the rate of aging through a unique role in kinase signaling, in addition to promoting proteostasis. They suggest a novel mode of regulation of the conserved nutrient-sensing cascade PKA that bypasses conventional signaling via the second messenger cAMP, and impinges on both H2O2 resistance and aging
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