20S Proteasome Hyperactivation enhances translation, lipid metabolism, proteostasis and longevity: a Proteo-transcriptimic analysis
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PROVIDER: PRJNA1081757 | ENA |
REPOSITORIES: ENA
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Project description:Our study elucidates the broad-spectrum effects of proteasome hyperactivation on the proteome, demonstrating its substantial influence on the proteostasis network. Through comprehensive analyses, we identified a significant reorganization of the transcriptome, enhanced mRNA processing, and increased translation activity. The study further reveals the hyperactivation's impact on intrinsically disordered proteins, lipid synthesis, and biogenesis, evidenced by major changes in lipid droplets and peroxisome proliferation. Notably, we uncovered protective phenotypes against oxidative stress, primarily mediated by Super Oxide Dismutases (SODs), indicating an elevated stress response readiness. Additionally, our research highlighted the hyperactive proteasome's selective targeting of vitellogenins, crucial for lipid metabolism and implicated in the aging process of C. elegans. Enhanced ERAD-dependent degradation was observed, facilitating the clearance of senescent VIT-2 protein aggregates and promoting healthier aging. The α3ΔN mutant significantly reduced the quantity of human alpha-1 antitrypsin (ATZ) aggregates and delayed their formation in a C. elegans model for ATZ disease, suggesting its potential as an ERAD enhancer. These findings propose proteasome hyperactivation as a promising strategy for treating aggregation-prone diseases, offering novel avenues for drug development and therapeutic interventions against neurodegeneration.
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Project description:Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first map proteasome-associated genetic co-dependencies. We identify cytosolic heat shock protein 70 (HSP70) chaperones as a potential target, consistent with proposed mechanisms of myeloma tumor cells overcoming PI-induced stress. These results led us to explore allosteric HSP70 inhibitors as myeloma therapeutics. We show these compounds exhibit increased efficacy against both acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Surprisingly, shotgun and pulsed-SILAC proteomics reveal that JG’s overcome PI resistance not via the expected mechanism of inhibiting cytosolic HSP70s, but instead through mitochondrial-localized HSP70, HSPA9, destabilizing the 55S mitoribosome. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize dynamics of myeloma proteostasis networks under therapeutic pressure while further motivating investigation of HSPA9 as a specific target in PI-resistant disease.
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Project description:The balance between protein synthesis and protein breakdown is known as protein homeostasis (proteostasis) and loss of proteostasis is one of the Hallmarks of Aging. The latter is maybe best illustrated by the fact that many age-related diseases like Parkinson’s and Alzheimer’s are characterized by the appearance of protein aggregates. However, very few studies actually measure protein half-life, and hence the observed lowered protein translation rates in many longevity models do not necessarily mean that the combined rate of synthesis and degradation (i.e. proteostasis) is lost or changed. To get a better insight in the actual changes in proteostasis of each protein in the proteome we have developed a quantitative mass-spectrometry based method that allows for the estimation of the half-life of each individual protein in the proteome and that is suitable for use in C. elegans. We have used this method to determine protein half-lives in developing C. elegans models of longevity and age-related disease and found that proteostasis, as measured by proteome-wide protein half-life is indeed dramatically changed in these models. However, the observed changes are in some cases unexpected and suggest that the combined rate of protein synthesis and breakdown does not necessarily correlate with eventual lifespan or healthspan. Furthermore, we show that the proteostasis network has a remarkable plasticity; in the tested models large changes in protein half-life are observed in the entire proteome rather than in a subset of proteins, thereby largely balancing the relative rate at which various biological processes proceed. Lastly, our data indicate that proteostasis is regulated at the level of the whole organism rather than at the single cell level. The here described method and observations are a start to further unravel how proteostasis and healthy aging are intertwined.
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