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Proteasome-mediated Processing of Nrf1 is Essential for Coordinate Induction of All Proteasome Subunits and P97

Overview
Journal Curr Biol
Publisher Cell Press
Specialty Biology
Date 2014 Jul 8
PMID 24998528
Citations 123
Authors
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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.

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References
1.
Dantuma N, Hoppe T . Growing sphere of influence: Cdc48/p97 orchestrates ubiquitin-dependent extraction from chromatin. Trends Cell Biol. 2012; 22(9):483-91. DOI: 10.1016/j.tcb.2012.06.003. View

2.
Berko D, Tabachnick-Cherny S, Shental-Bechor D, Cascio P, Mioletti S, Levy Y . The direction of protein entry into the proteasome determines the variety of products and depends on the force needed to unfold its two termini. Mol Cell. 2012; 48(4):601-11. PMC: 5603081. DOI: 10.1016/j.molcel.2012.08.029. View

3.
Stewart D, Killeen E, Naquin R, Alam S, Alam J . Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium. J Biol Chem. 2002; 278(4):2396-402. DOI: 10.1074/jbc.M209195200. View

4.
Kisselev A, Callard A, Goldberg A . Importance of the different proteolytic sites of the proteasome and the efficacy of inhibitors varies with the protein substrate. J Biol Chem. 2006; 281(13):8582-90. DOI: 10.1074/jbc.M509043200. View

5.
Tsuchiya Y, Morita T, Kim M, Iemura S, Natsume T, Yamamoto M . Dual regulation of the transcriptional activity of Nrf1 by β-TrCP- and Hrd1-dependent degradation mechanisms. Mol Cell Biol. 2011; 31(22):4500-12. PMC: 3209242. DOI: 10.1128/MCB.05663-11. View