title: TCF11/Nrf1-Mediated Induction of Proteasome Expression Prevents Cytotoxicity by Rotenone.
abstract: Precise regulation of cellular protein degradation is essential for maintaining protein and redox homeostasis. The ubiquitin proteasome system (UPS) represents one of the major degradation machineries, and UPS disturbances are strongly associated with neurodegeneration. We have previously shown that the transcription factor TCF11/Nrf1 induces antioxidant response element-mediated upregulation of UPS components in response to proteotoxic stress. Knockout of TCF11/Nrf1 is embryonically lethal, and therefore, the present investigation describes the role of oxidative stress in regulating TCF11/Nrf1-dependent proteasome expression in a model system relevant to Parkinson's disease.
  
  
  
  Using the human dopaminergic neuroblastoma cell line SH-SY5Y and mouse nigrostriatal organotypic slice cultures, gene and protein expression analysis and functional assays revealed oxidative stress is induced by the proteasome inhibitor epoxomicin or the mitochondrial complex I inhibitor rotenone and promotes the upregulation of proteasome expression and function mediated by TCF11/Nrf1 activation. In addition, we show that these stress conditions induce the unfolded protein response. TCF11/Nrf1, thus, has a cytoprotective function in response to oxidative and proteotoxic stress. Innovation and Conclusion: We here demonstrate that adaption of the proteasome system in response to oxidative stress is dependent on TCF11/Nrf1 in this model system. We conclude that TCF11/Nrf1, therefore, plays a vital role in maintaining redox and protein homeostasis. This work provides a vital insight into the molecular mechanisms of neurodegeneration due to oxidative stress by rotenone, and further studies investigating the role of TCF11/Nrf1 in the human condition would be of considerable interest. Antioxid. Redox Signal. 25, 870-885.
authors.affiliation: 1 Charité-Universitätsmedizin Berlin, Institut für Biochemie , Berlin, Germany .
authors.forename: Franziska
authors.initials: F
authors.lastname: Sotzny
authors.affiliation: 1 Charité-Universitätsmedizin Berlin, Institut für Biochemie , Berlin, Germany .
authors.forename: Eileen
authors.initials: E
authors.lastname: Schormann
authors.affiliation: 1 Charité-Universitätsmedizin Berlin, Institut für Biochemie , Berlin, Germany .
authors.forename: Ina
authors.initials: I
authors.lastname: Kühlewindt
authors.affiliation: 1 Charité-Universitätsmedizin Berlin, Institut für Biochemie , Berlin, Germany .
authors.forename: Annett
authors.initials: A
authors.lastname: Koch
authors.affiliation: 1 Charité-Universitätsmedizin Berlin, Institut für Biochemie , Berlin, Germany .
authors.forename: Anja
authors.initials: A
authors.lastname: Brehm
authors.affiliation: 2 Translational Autoinflammatory Disease Section , NIAMS, NIH, Bethesda, Maryland.
authors.forename: Raphaela
authors.initials: R
authors.lastname: Goldbach-Mansky
authors.affiliation: 1 Charité-Universitätsmedizin Berlin, Institut für Biochemie , Berlin, Germany .
authors.forename: Kate E
authors.initials: KE
authors.lastname: Gilling
authors.affiliation: 1 Charité-Universitätsmedizin Berlin, Institut für Biochemie , Berlin, Germany .
authors.forename: Elke
authors.initials: E
authors.lastname: Krüger
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008954:Models, Biological; D051265:NF-E2-Related Factor 1 / Q000235:genetics / Q000378:metabolism*; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology*
chemical_list: D051265:NF-E2-Related Factor 1; C088357:NFE2L1 protein, human; D051266:Nuclear Respiratory Factor 1; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D012402:Rotenone; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin
keywords: neurodegeneration; oxidative stress; proteasome; rotenone; transcription factor TCF11/Nrf1; ubiquitin