Dataset Information

Proteasome ?5 subunit overexpression improves proteostasis during aging and extends lifespan in Drosophila melanogaster.

ABSTRACT: The ?5 subunit of the proteasome has been shown in worms and in human cell lines to be regulatory. In these models, ?5 overexpression results in upregulation of the entire proteasome complex which is sufficient to increase proteotoxic stress resistance, improve metabolic parameters, and increase longevity. However, fundamental questions remain unanswered, including the temporal requirements for ?5 overexpression and whether ?5 overexpression can extend lifespan in other species. To determine if adult-only overexpression of the ?5 subunit can increase proteasome activity in a different model, we characterized phenotypes associated with ?5 overexpression in Drosophila melanogaster adults. We find that adult-only overexpression of the ?5 subunit does not result in transcriptional upregulation of the other subunits of the proteasome as they do in nematodes and human cell culture. Despite this lack of a regulatory role, boosting ?5 expression increases the chymotrypsin-like activity associated with the proteasome, reduces both the size and number of ubiquitinated protein aggregates in aged flies, and increases longevity. Surprisingly, these phenotypes were not associated with increased resistance to acute proteotoxic insults or improved metabolic parameters.

SUBMITTER: Nguyen NN

PROVIDER: S-EPMC6395709 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Proteasome β5 subunit overexpression improves proteostasis during aging and extends lifespan in Drosophila melanogaster.

Nguyen Nga N NN Rana Anil A Goldman Camille C Moore Rhiannon R Tai Justin J Hong Yongchan Y Shen Jingyi J Walker David W DW Hur Jae H JH

Scientific reports 20190228 1

The β5 subunit of the proteasome has been shown in worms and in human cell lines to be regulatory. In these models, β5 overexpression results in upregulation of the entire proteasome complex which is sufficient to increase proteotoxic stress resistance, improve metabolic parameters, and increase longevity. However, fundamental questions remain unanswered, including the temporal requirements for β5 overexpression and whether β5 overexpression can extend lifespan in other species. To determine if ...[more]

PMID: 30816680

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Project description: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.

Dataset Information

Proteasome ?5 subunit overexpression improves proteostasis during aging and extends lifespan in Drosophila melanogaster.

Publications

Proteasome β5 subunit overexpression improves proteostasis during aging and extends lifespan in Drosophila melanogaster.

Similar Datasets

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