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Elevated proteasome capacity extends replicative lifespan in Saccharomyces cerevisiae

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Item Type:Article
Title:Elevated proteasome capacity extends replicative lifespan in Saccharomyces cerevisiae
Creators Name:Kruegel, U. and Robison, B. and Dange, T. and Kahlert, G. and Delaney, J.R. and Kotireddy, S. and Tsuchiya, M. and Tsuchiyama, S. and Murakami, C.J. and Schleit, J. and Sutphin, G. and Carr, D. and Tar, K. and Dittmar, G. and Kaeberlein, M. and Kennedy, B.K. and Schmidt, M.
Abstract:Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining repair and elimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent. Proof for a direct impact of enhanced proteasome function on longevity, however, is still lacking. To determine the importance of proteasome function in yeast aging, we established a method to modulate UPS capacity by manipulating levels of the UPS-related transcription factor Rpn4. While cells lacking RPN4 exhibit a decreased non-adaptable proteasome pool, loss of UBR2, an ubiquitin ligase that regulates Rpn4 turnover, results in elevated Rpn4 levels, which upregulates UPS components. Increased UPS capacity significantly enhances replicative lifespan (RLS) and resistance to proteotoxic stress, while reduced UPS capacity has opposing consequences. Despite tight transcriptional co-regulation of the UPS and oxidative detoxification systems, the impact of proteasome capacity on lifespan is independent of the latter, since elimination of Yap1, a key regulator of the oxidative stress response, does not affect lifespan extension of cells with higher proteasome capacity. Moreover, since elevated proteasome capacity results in improved clearance of toxic huntingtin fragments in a yeast model for neurodegenerative diseases, we speculate that the observed lifespan extension originates from prolonged elimination of damaged proteins in old mother cells. Epistasis analyses indicate that proteasome-mediated modulation of lifespan is at least partially distinct from dietary restriction, Tor1, and Sir2. These findings demonstrate that UPS capacity determines yeast RLS by a mechanism that is distinct from known longevity pathways and raise the possibility that interventions to promote enhanced proteasome function will have beneficial effects on longevity and age-related disease in humans.
Keywords:DNA Replication, DNA-Binding Proteins, Fungal Gene Expression Regulation, Oxidative Stress, Phosphatidylinositol 3-Kinases, Proteasome Endopeptidase Complex, Saccharomyces cerevisiae, Saccharomyces Silent Information Regulator Proteins, Sirtuin 2, Transcription Factors, Transcriptional Activation, Ubiquitin, Ubiquitin-Protein Ligases
Source:PLoS Genetics
Publisher:Public Library of Science
Page Range:e1002253
Date:September 2011
Official Publication:https://doi.org/10.1371/journal.pgen.1002253
PubMed:View item in PubMed

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