DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment
Ran-Der Hwang,
YuNing Lu,
Qing Tang,
Goran Periz,
Giho Park,
Xiangning Li,
Qiwang Xiang,
Yang Liu,
Tao Zhang,
Jiou Wang
Affiliations
Ran-Der Hwang
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Baltimore, United States; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, United States
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Baltimore, United States; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, United States
Qing Tang
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Baltimore, United States; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, United States
Goran Periz
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Baltimore, United States; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, United States
Giho Park
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Baltimore, United States; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, United States
Xiangning Li
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Baltimore, United States; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, United States
Qiwang Xiang
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Baltimore, United States; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, United States
Yang Liu
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Baltimore, United States; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, United States
Tao Zhang
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Baltimore, United States; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, United States
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Baltimore, United States; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, United States
Proteotoxic stress impairs cellular homeostasis and underlies the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The proteasomal and autophagic degradation of proteins are two major pathways for protein quality control in the cell. Here, we report a genome-wide CRISPR screen uncovering a major regulator of cytotoxicity resulting from the inhibition of the proteasome. Dihydrolipoamide branched chain transacylase E2 (DBT) was found to be a robust suppressor, the loss of which protects against proteasome inhibition-associated cell death through promoting clearance of ubiquitinated proteins. Loss of DBT altered the metabolic and energetic status of the cell and resulted in activation of autophagy in an AMP-activated protein kinase (AMPK)-dependent mechanism in the presence of proteasomal inhibition. Loss of DBT protected against proteotoxicity induced by ALS-linked mutant TDP-43 in Drosophila and mammalian neurons. DBT is upregulated in the tissues of ALS patients. These results demonstrate that DBT is a master switch in the metabolic control of protein quality control with implications in neurodegenerative diseases.