Lifespan Control by Redox-Dependent Recruitment of Chaperones to Misfolded Proteins.
Caloric restriction (CR) extends the lifespan of flies, worms, and yeast by counteracting age-related oxidation of H2O2-scavenging peroxiredoxins (Prxs). Here, we show that increased dosage of the major cytosolic Prx in yeast, Tsa1, extends lifespan in an Hsp70 chaperone-dependent and CR-independent manner without increasing H2O2 scavenging or genome stability. We found that Tsa1 and Hsp70 physically interact and that hyperoxidation of Tsa1 by H2O2 is required for the recruitment of the Hsp70 chaperones and the Hsp104 disaggregase to misfolded and aggregated proteins during aging, but not heat stress. Tsa1 counteracted the accumulation of ubiquitinated aggregates during aging and the reduction of hyperoxidized Tsa1 by sulfiredoxin facilitated clearance of H2O2-generated aggregates. The data reveal a conceptually new role for H2O2 signaling in proteostasis and lifespan control and shed new light on the selective benefits endowed to eukaryotic peroxiredoxins by their reversible hyperoxidation.
Department of Chemistry and Molecular Biology (CMB), University of Gothenburg, Medicinaregatan 9C, 413 90 Göteborg, Sweden; Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 7A, 413 90 Göteborg, Sweden.
Sarah
S
Hanzén
Department of Chemistry and Molecular Biology (CMB), University of Gothenburg, Medicinaregatan 9C, 413 90 Göteborg, Sweden; Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 7A, 413 90 Göteborg, Sweden.
Katarina
K
Vielfort
Department of Chemistry and Molecular Biology (CMB), University of Gothenburg, Medicinaregatan 9C, 413 90 Göteborg, Sweden.
Junsheng
J
Yang
Department of Chemistry and Molecular Biology (CMB), University of Gothenburg, Medicinaregatan 9C, 413 90 Göteborg, Sweden.
Friederike
F
Roger
Department of Chemistry and Molecular Biology (CMB), University of Gothenburg, Medicinaregatan 9C, 413 90 Göteborg, Sweden.
Veronica
V
Andersson
Department of Chemistry and Molecular Biology (CMB), University of Gothenburg, Medicinaregatan 9C, 413 90 Göteborg, Sweden.
Sara
S
Zamarbide-Forés
Department of Chemistry and Molecular Biology (CMB), University of Gothenburg, Medicinaregatan 9C, 413 90 Göteborg, Sweden; Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 7A, 413 90 Göteborg, Sweden.
Rebecca
R
Andersson
Department of Chemistry and Molecular Biology (CMB), University of Gothenburg, Medicinaregatan 9C, 413 90 Göteborg, Sweden.
Lisa
L
Malm
Oxidative Stress and Cancer, IBITECS, SBIGEM, CEA-Saclay, 91191 Gif-sur-Yvette, France.
Gael
G
Palais
Oxidative Stress and Cancer, IBITECS, SBIGEM, CEA-Saclay, 91191 Gif-sur-Yvette, France; School of Medicine and Dentistry, University of Rochester Medical Center, 601 Elmwood Avenue, Box 633, Rochester, NY 14642, USA.
Benoît
B
Biteau
Department of Chemistry and Molecular Biology (CMB), University of Gothenburg, Medicinaregatan 9C, 413 90 Göteborg, Sweden.
Beidong
B
Liu
Oxidative Stress and Cancer, IBITECS, SBIGEM, CEA-Saclay, 91191 Gif-sur-Yvette, France.
Michel B
MB
Toledano
Department of Chemistry and Molecular Biology (CMB), University of Gothenburg, Medicinaregatan 9C, 413 90 Göteborg, Sweden. Electronic address: mikael.molin@cmb.gu.se.
Mikael
M
Molin
Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 7A, 413 90 Göteborg, Sweden. Electronic address: thomas.nystrom@cmb.gu.se.
Thomas
T
Nyström
D000818:Animals; D031204:Caloric Restriction; D042822:Genomic Instability; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008136:Longevity; D010084:Oxidation-Reduction; D010544:Peroxidases / Q000378:metabolism*; D066329:Protein Aggregates; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015398:Signal Transduction
D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D066329:Protein Aggregates; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae; D006861:Hydrogen Peroxide; D010544:Peroxidases; C496253:Tsa1 protein, S cerevisiae