20S Proteasome Hyperactivation enhances translation, lipid metabolism, proteostasis and longevity: a Proteo-transcriptimic analysis

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 a3?N 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. Overall design: Total mRNA was extracted from age synchronized C.elegans populations . In total 5 replicates Wild types and 5 replicates Hyperactive proteasome mutants from Day 8 adults were used for sequencing.