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

Abstract

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 adult-only overexpression of the β5 subunit can increase proteasome activity in a different model, we characterized phenotypes associated with β5 overexpression in Drosophila melanogaster adults. We find that adult-only overexpression of the β5 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 β5 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.

Neuronal‐specific proteasome augmentation via Prosβ5 overexpression extends lifespan and reduces age‐related cognitive decline

“…In addition, we did not observe any improvements in healthspan and instead found reduced spontaneous activity in middle‐aged flies providing some indication of toxicity (Figure h). Our findings conflict with a recent report that Prosβ5 under control of Da‐GS‐GAL4 extends lifespan (Nguyen et al, ). We note that a considerably lower dose of RU486 was employed in the study by Nguyen and colleagues (~23 μM in contrast to 200 μM in the present study).…”

Proteasome subunit α1 overexpression preferentially drives canonical proteasome biogenesis and enhances stress tolerance in yeast

“…There are multiple reports demonstrating the importance of subunit stoichiometry in proteasome assembly and cell health. In Drosophila melanogaster , the overexpression of the CP subunit β5 has been reported to significantly increase proteasome assembly and extend the lifespan of flies 34 . Similarly, increased expression of the RP subunit Rpn6 (PSMD11 in humans) has been demonstrated to enhance 26S proteasome formation and increase the longevity of human embryonic stem cells 35 .…”

ER-Resident Transcription Factor Nrf1 Regulates Proteasome Expression and Beyond

“…In these organisms, the Nrf/cap 'n' collar (Cnc) transcription factors, CncC (D. melanogaster), SKN-1 (C. elegans), and Nrf1 (mammal) are responsible for the expression of proteasome subunit genes, especially in the compensatory response (termed as the bounce-back response) [16,17,41,45] (Figure 2). Overexpression of certain proteasome subunits also upregulates 26S proteasome activity, resulting in lifespan extension in C. elegans and fruit flies, although its exact mechanism remains elusive [46][47][48][49][50][51]. Increasing the proteasome abundance when needed is important for sustaining protein degradation and cell viability, as the proteasome is essential for a broad range of housekeeping functions.…”