Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways.
Kelsey L HickeyAlexandra PanovEnya Miguel WhelanTillman SchäferArda MizrakRon R KopitoWolfgang BaumeisterRubén Fernández-BusnadiegoJ Wade HarperPublished in: bioRxiv : the preprint server for biology (2024)
A hallmark of neurodegenerative diseases such as Parkinson's Disease is the progressive loss of proteostasis, leading to conversion of proteins from productive folding pathways to populate aggregation-prone misfolded (non-native or intermediate) states. To combat this toxicity, cells have evolved degradation pathways (ubiquitin-proteasome system and autophagy) that detect and degrade misfolded proteins. Here, we find that aggregation burden dictates the activation of proteasome-dependent quality control pathways. Initial misfolded proteins, enriched in oligomers, utilize UBE3C-dependent proteasomal degradation, while higher aggregation levels, enriched in larger insoluble structures, activate the NRF1 transcription factor to increase proteasome subunit transcription, and subsequent degradation capacity of cells. The role of UBE3C and NRF1 in aggregation clearance may provide therapeutic targets aimed to preventing neurodegenerative disease.
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