title: Proteasome-mediated processing of Nrf1 is essential for coordinate induction of all proteasome subunits and p97.
abstract: BACKGROUND
  Proteasome inhibitors are widely used in the treatment of multiple myeloma and as research tools. Additionally, diminished proteasome function may contribute to neuronal dysfunction. In response to these inhibitors, cells enhance the expression of proteasome subunits by the transcription factor Nrf1. Here, we investigate the mechanisms by which decreased proteasome function triggers production of new proteasomes via Nrf1.
  
  
  RESULTS
  Exposure of myeloma or neuronal cells to proteasome inhibitors (bortezomib, epoxomicin, and MG132), but not to proteotoxic or ER stress, caused a 2- to 4-fold increase within 4 hr in mRNAs for all 26S subunits. In addition, p97 and its cofactors (Npl4, Ufd1, and p47), PA200, and USP14 were induced, but expression of immunoproteasome-specific subunits was suppressed. Nrf1 mediates this induction of proteasomes and p97, but only upon exposure to low concentrations of inhibitors that partially inhibit proteolysis. Surprisingly, high concentrations of these inhibitors prevent this compensatory response. Nrf1 is normally ER-bound, and its release requires its deglycosylation and ubiquitination. Normally ubiquitinated Nrf1 is rapidly degraded, but when partially inhibited, proteasomes carry out limited proteolysis and release the processed Nrf1 (lacking its N-terminal region) from the ER, which allows it to enter the nucleus and promote gene expression.
  
  
  CONCLUSIONS
  When fully active, proteasomes degrade Nrf1, but when partially inhibited, they perform limited proteolysis that generates the active form of Nrf1. This elegant mechanism allows cells to compensate for reduced proteasome function by enhancing production of 26S subunits and p97.
authors.affiliation: Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Sha
authors.affiliation: Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA. Electronic address: alfred_goldberg@hms.harvard.edu.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
mesh_terms: D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D009687:Nuclear Proteins / Q000096:biosynthesis; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D059748:Proteolysis; D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D043222:Ubiquitin Thiolesterase / Q000096:biosynthesis; D054875:Ubiquitination; D056811:Unfolded Protein Response
chemical_list: D001897:Boronic Acids; D000069286:Bortezomib; D007976:Leupeptins; D009687:Nuclear Proteins; D051266:Nuclear Respiratory Factor 1; D009842:Oligopeptides; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D011719:Pyrazines; D034741:RNA, Small Interfering; D043222:Ubiquitin Thiolesterase; C495633:NRF1 protein, human; C509299:USP14 protein, human; C521188:PSME4 protein, human; C061553:ATP dependent 26S protease; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C078846:epoxomicin