Proteasome-mediated processing of Nrf1 is essential for coordinate induction of all proteasome subunits and p97
Open accessAbstract
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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Nrf1-mediated transcriptional upregulation of the proteasome occurs during proteasome impairment to compensate for reduced proteasome function.
“This may be explained by the Nrf1-mediated transcriptional upregulation of the proteasome during proteasome impairment to compensate for reduced proteasome function [31].”
From PSMC5 insufficiency and P320R mutation impair proteasome function (2024) · cites this paper as [31]
Some compensation mechanisms are only observed under low concentrations of proteasome inhibitors and are absent under high levels of inhibition.
“Interestingly, some of these compensation mechanisms are only observed under low concentrations of proteasome inhibitors, and are absent under high levels of inhibition (Sha and Goldberg, 2014)”
From Altered Phosphorylation of the Proteasome Subunit Rpt6 Has Minimal Impact on Synaptic Plasticity and Learning (2021) · cites this paper as Sha and Goldberg, 2014
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“Interestingly, some of these compensation mechanisms are only observed under low concentrations of proteasome inhibitors, and are absent under high levels of inhibition (Sha & Goldberg, 2014), indicating specialized compensatory mechanisms for minor alterations in activity.”
BackgroundPSMC5 insufficiency and P320R mutation impair proteasome function
Yu, Z.-Q., Carmichael, J., Collins, G. A., D'Agostino, M. D., Lessard, M., Firth, H. V., Harijan, P., Fry, A. E., Dean, J., Zhang, J., et al. (2024) · Human Molecular Genetics · doi:10.1093/hmg/ddae085 · Cited by 4 · see citing works
“As proteasome defects lead to compensatory responses like activation of autophagy, the integrated stress response, and Nrf1 transcriptional programmes [31, 39, 40], it is possible that some of the consequences of these proteasome mutations may be driven by hyperactive compensatory programmes.”
Self-citation
- Authors
- Sha, Z., & Goldberg, A. L.
- Affiliations
- Harvard University (US)
- Corresponding author
- Goldberg, Alfred L.
- ORCID
- Goldberg, Alfred L.
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 24
- Issue
- 14
- Pages
- 1573-1583
- ISSN
- 0960-9822 (ISSN-L)
- PMC
- PMC4108618
- OpenAlex
- W2075939049
- Cited by
- 215
- References
- 50
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 13 · 2023: 13 · 2022: 20 · 2021: 15 · 2020: 23 · 2019: 25 · 2018: 18 · 2017: 20 · 2016: 27 · 2015: 15 · 2014: 5
- FWCI
- 9.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Leukemia and Lymphoma Society
- National Institute of General Medical Sciences (GM051923-18, R01GM051923)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- NRF1, proteasome, VCP, proteasome inhibitors, bortezomib, epoxomicin, MG132, limited proteolysis, ubiquitination, deglycosylation, endoplasmic reticulum, compensatory response, multiple myeloma, neurons, immunoproteasome, Npl4, Ufd1, p47phox, PA200, USP14
- MeSH terms
- Bortezomib, Boronic Acids, Cell Line, Endoplasmic Reticulum, Humans, Leupeptins, Nuclear Proteins, Oligopeptides, Pyrazines, RNA Interference, RNA, Small Interfering, Ubiquitin Thiolesterase, Proteasome Endopeptidase Complex, Nuclear Respiratory Factor 1, Ubiquitination, Unfolded Protein Response, HEK293 Cells, Proteolysis, Proteasome Inhibitors
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