Regulation of Protein Quality Control by UBE4B and LSD1 through p53-Mediated Transcription

Protein quality control is essential for clearing misfolded and aggregated proteins from the cell,and its failure is associated with many neurodegenerative disorders. here,we identify two genes,ufd-2 and spr-5,that when inactivated,synergistically and robustly suppress neurotoxicity associated with misfolded proteins in caenorhabditis elegans. loss of human orthologs ubiquitination factor e4 b (ube4b) and lysine-specific demethylase 1 (lsd1),respectively encoding a ubiquitin ligase and a lysine-specific demethylase,promotes the clearance of misfolded proteins in mammalian cells by activating both proteasomal and autophagic degradation machineries. an unbiased search in this pathway reveals a downstream effector as the transcription factor p53,a shared substrate of ube4b and lsd1 that functions as a key regulator of protein quality control to protect against proteotoxicity. these studies identify a new protein quality control pathway via regulation of transcription factors and point to the augmentation of protein quality control as a wide-spectrum antiproteotoxicity strategy. © 2015 periz et al.