title: Stringent Control of NFE2L3 (Nuclear Factor, Erythroid 2-Like 3; NRF3) Protein Degradation by FBW7 (F-box/WD Repeat-containing Protein 7) and Glycogen Synthase Kinase 3 (GSK3).
abstract: The NFE2L3 transcription factor has been implicated in various cellular processes, including carcinogenesis, stress response, differentiation, and inflammation. Previously it has been shown that NFE2L3 has a rapid turnover and is stabilized by proteasomal inhibitors. The mechanisms regulating the degradation of this protein have not been investigated. Here we report ubiquitination of NFE2L3 and demonstrate that F-box/WD repeat-containing protein 7 (FBW7 or FBWX7), a component of Skp1, Cullin 1, F-box containing complex (SCF)-type E3 ligase, is the E3 ligase mediating the degradation of NFE2L3. We showed that FBW7 interacts with NFE2L3 and that dimerization of FBW7 is required for the degradation of the transcription factor. We also demonstrate that the kinase glycogen synthase kinase 3 (GSK3) mediates the FBW7-dependent ubiquitination of NFE2L3. We show phosphorylation of NFE2L3 by GSK3 and its significance in the regulation of NFE2L3 by the tumor suppressor FBW7. FBW7 abrogated NFE2L3-mediated repression of the
  quinone oxidoreductase 1 (NQO1) gene antioxidant response element (ARE). Our findings reveal FBW7 and GSK3 as novel regulators of the NFE2L3 transcription factor and a potential mechanism by which FBW7 might regulate detoxification and the cellular response to stress.
authors: From the Lady Davis Institute for Medical Research.
authors: Meenakshi B
authors: MB
authors: Kannan
authors: From the Lady Davis Institute for Medical Research.
authors: Isadore
authors: I
authors: Dodard-Friedman
authors: From the Lady Davis Institute for Medical Research, Department of Medicine, and Department of Physiology, McGill University, Montreal, Quebec H3T 1E2, Canada volker.blank@mcgill.ca.
authors: Volker
authors: V
authors: Blank
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C117963:NFE2L3 protein, human; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex
keywords: E3 ubiquitin ligase; FBW7; GSK3; NFE2L3; oxidative stress; protein degradation; ubiquitin; ubiquitin ligase; ubiquitination