title: Regulation of protein quality control by UBE4B and LSD1 through p53-mediated transcription.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology and Department of Neuroscience, Bloomberg School of Public Health and School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Goran
authors.initials: G
authors.lastname: Periz
authors.affiliation: Department of Biochemistry and Molecular Biology and Department of Neuroscience, Bloomberg School of Public Health and School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology and Department of Neuroscience, Bloomberg School of Public Health and School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Biogen Idec, Cambridge, Massachusetts, United States of America.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kankel
authors.affiliation: Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Jablonski
authors.affiliation: Department of Neurology and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Kalb
authors.affiliation: Biogen Idec, Cambridge, Massachusetts, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: McCampbell
authors.affiliation: Department of Biochemistry and Molecular Biology and Department of Neuroscience, Bloomberg School of Public Health and School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Jiou
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001343:Autophagy; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011786:Quality Control; D013312:Stress, Physiological; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D014158:Transcription, Genetic / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D029742:Caenorhabditis elegans Proteins; C000606290:SOD1 protein, human; D016159:Tumor Suppressor Protein p53; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D046988:Proteasome Endopeptidase Complex
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