ArticleCurrent biology : CB2014
Proteasome-mediated processing of Nrf1 is essential for coordinate induction of all proteasome subunits and p97.
Article in Current biology : CB, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 133 papers.
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Who cites it
133 citing papers in PubMed, 219 citations in OpenAlex.
- Coordinated control of proteasome subunit gene expression promotes stress resistance, proteostasis, and longevity.GeroScience · 2026Article
- Stimulating proteasomal degradation in human proteinopathies.The FEBS journal · 2026Review
- The Nematicide Tioxazafen Disrupts Proteasome Function via Cytochrome P450 Bioactivation.bioRxiv : the preprint server for biology · 2026Article
- Proteasome Inhibition Amplifies Endoplasmic Reticulum (ER) Stress Responses: Comparative Proteomics of Chinese Hamster Ovary Cell Lines.Biomolecules · 2026Article
- NFE2L1/Nrf1 forms a coactivator complex post-peptide:Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Early proteasome downregulation and dysfunction drive proteostasis failure in Alzheimer's disease.Brain : a journal of neurology · 2025Article
- Disentangling cell-intrinsic and cell-extrinsic factors underlying evolution.Cell genomics · 2025Article
- Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma.Clinical and experimental medicine · 2025Review
- Activating the NFE2L1-ubiquitin-proteasome system by DDI2 protects from ferroptosis.Cell death and differentiation · 2025Article
- Nrf1 acts as a highly-conserved determinon for maintaining robust redox homeostasis in the eco-evo-devo process of life histories.Cell stress · 2025Review
- NFE2L1 as a central regulator of proteostasis in neurodegenerative diseases: interplay with autophagy, ferroptosis, and the proteasome.Frontiers in molecular neuroscience · 2025Review
- PSMC5 insufficiency and P320R mutation impair proteasome function.Human molecular genetics · 2024Article
- Ferroptosis regulation by Cap'n'collar family transcription factors.The Journal of biological chemistry · 2024Review
- Understanding the Transcription Factor NFE2L1/NRF1 from the Perspective of Hallmarks of Cancer.Antioxidants (Basel, Switzerland) · 2024Review
- Article
- Domains in Action: Understanding Ddi1's Diverse Functions in the Ubiquitin-Proteasome System.International journal of molecular sciences · 2024Review
- Knockout of PA200 improves proteasomal degradation and myelination in a proteotoxic neuropathy.Life science alliance · 2024Article
- Review
- A novel autism-associated UBLCP1 mutation impacts proteasome regulation/activity.Translational psychiatry · 2023Article
- Proximity proteomic analysis of the NRF family reveals the Parkinson's disease protein ZNF746/PARIS as a co-complexed repressor of NRF2.Science signaling · 2023Article
73 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
backgroundProteasome 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.
resultsExposure 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.
conclusionsWhen 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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.