Lifespan Control by Redox-Dependent Recruitment of Chaperones to Misfolded Proteins

• Published in: Cell Vol. 166; no. 1; pp. 140 - 151
• Main Authors: Hanzén, Sarah, Vielfort, Katarina, Yang, Junsheng, Roger, Friederike, Andersson, Veronica, Zamarbide-Forés, Sara, Andersson, Rebecca, Malm, Lisa, Palais, Gael, Biteau, Benoît, Liu, Beidong, Toledano, Michel B., Molin, Mikael, Nyström, Thomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.06.2016; Elsevier
• Subjects: Animals; asymmetric inheritance; Biochemistry & Molecular Biology; Biological Sciences; Biologiska vetenskaper; budding; Caloric Restriction; Cell Biology; damaged proteins; genome instability; Genomic Instability; Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - metabolism; human lung-cancer; Humans; Hydrogen Peroxide - metabolism; hydrogen-peroxide; Life Sciences; Longevity; Oxidation-Reduction; oxidative stress; Peroxidases - metabolism; peroxiredoxin tsa1; Protein Aggregates; Protein Folding; quality-control; Saccharomyces cerevisiae - cytology; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; saccharomyces-cerevisiae; Signal Transduction; yeast; Protein Aggregates; Genomic Instability; Signal Transduction; Oxidation-Reduction; Caloric Restriction; Humans; Hydrogen Peroxide; Longevity; Protein Folding; Animals; Peroxidases; Heat-Shock Proteins; Saccharomyces cerevisiae Proteins; Saccharomyces cerevisiae; HSP70 Heat-Shock Proteins
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.05.006

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. [Display omitted] •Increased peroxiredoxin Tsa1 levels extend lifespan in a chaperone-dependent manner•A redox switch in Tsa1 recruits Hsp70 and Hsp104 to misfolded proteins during aging•Disaggregation of misfolded proteins requires enzyme-dependent reduction of Tsa1•Distinct chaperone pathways recognize protein aggregates on H2O2 stress and heat shock Lifespan extension in yeast in the absence of calorie restriction is mediated by conserved redox-regulated enzymes that recruit chaperones to misfolded proteins in aggregates.