Proteasome hyperactivation rewires the proteome enhancing stress resistance, proteostasis, lipid metabolism and ERAD in .

Proteasome dysfunction is implicated in the pathogenesis of neurodegenerative diseases and age-related proteinopathies. Using a model, we demonstrate that 20S proteasome hyperactivation, facilitated by 20S gate-opening, accelerates the targeting of intrinsically disordered proteins. This leads to increased protein synthesis, extensive rewiring of the proteome and transcriptome, enhanced oxidative stress defense, accelerated lipid metabolism, and peroxisome proliferation.