title: Frequency Modulated Translocational Oscillations of Nrf2 Mediate the Antioxidant Response Element Cytoprotective Transcriptional Response.
abstract: OBJECTIVE
  Stress responsive signaling coordinated by nuclear factor erythroid 2-related factor 2 (Nrf2) provides an adaptive response for protection of cells against toxic insults, oxidative stress and metabolic dysfunction. Nrf2 regulates a battery of protective genes by binding to regulatory antioxidant response elements (AREs). The aim of this study was to examine how Nrf2 signals cell stress status and regulates transcription to maintain homeostasis.
  
  
  RESULTS
  In live cell microscopy we observed that Nrf2 undergoes autonomous translocational frequency-modulated oscillations between cytoplasm and nucleus. Oscillations occurred in quiescence and when cells were stimulated at physiological levels of activators, they decrease in period and amplitude and then evoke a cytoprotective transcriptional response. We propose a mechanism whereby oscillations are produced by negative feedback involving successive de-phosphorylation and phosphorylation steps. Nrf2 was inactivated in the nucleus and reactivated on return to the cytoplasm. Increased frequency of Nrf2 on return to the cytoplasm with increased reactivation or refresh-rate under stress conditions activated the transcriptional response mediating cytoprotective effects. The serine/threonine-protein phosphatase PGAM5, member of the Nrf2 interactome, was a key regulatory component.
  
  
  METHODS
  We found that Nrf2 is activated in cells without change in total cellular Nrf2 protein concentration. Regulation of ARE-linked protective gene transcription occurs rather through translocational oscillations of Nrf2. We discovered cytoplasmic refresh rate of Nrf2 is important in maintaining and regulating the transcriptional response and links stress challenge to increased cytoplasmic surveillance. We found silencing and inhibition of PGAM5 provides potent activation of Nrf2.
  
  
  CONCLUSIONS
  Frequency modulated translocational oscillations of Nrf2 mediate the ARE-linked cytoprotective transcriptional response.
authors.affiliation: 1 Clinical Sciences Research Laboratories, Warwick Medical School, University Hospital , University of Warwick, Coventry, United Kingdom .
authors.forename: Mingzhan
authors.initials: M
authors.lastname: Xue
authors.affiliation: 2 Warwick Systems Biology Centre, University of Warwick , Coventry, United Kingdom .
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Momiji
authors.affiliation: 1 Clinical Sciences Research Laboratories, Warwick Medical School, University Hospital , University of Warwick, Coventry, United Kingdom .|2 Warwick Systems Biology Centre, University of Warwick , Coventry, United Kingdom .
authors.forename: Naila
authors.initials: N
authors.lastname: Rabbani
authors.affiliation: 3 School of Life Sciences, University of Warwick , Wellesbourne, United Kingdom .
authors.forename: Guy
authors.initials: G
authors.lastname: Barker
authors.affiliation: 2 Warwick Systems Biology Centre, University of Warwick , Coventry, United Kingdom .
authors.forename: Till
authors.initials: T
authors.lastname: Bretschneider
authors.affiliation: 1 Clinical Sciences Research Laboratories, Warwick Medical School, University Hospital , University of Warwick, Coventry, United Kingdom .
authors.forename: Anatoly
authors.initials: A
authors.lastname: Shmygol
authors.affiliation: 2 Warwick Systems Biology Centre, University of Warwick , Coventry, United Kingdom .
authors.forename: David A
authors.initials: DA
authors.lastname: Rand
authors.affiliation: 1 Clinical Sciences Research Laboratories, Warwick Medical School, University Hospital , University of Warwick, Coventry, United Kingdom .|2 Warwick Systems Biology Centre, University of Warwick , Coventry, United Kingdom .
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Thornalley
mesh_terms: D061745:Antioxidant Response Elements; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D006801:Humans; D024101:Mitochondrial Proteins / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D021381:Protein Transport; D015533:Transcriptional Activation
chemical_list: D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C529563:PGAM5 protein, human; D010749:Phosphoprotein Phosphatases