Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells
Open accessAbstract
In Saccharomyces cerevisiae, chemical or genetic inhibition of proteasome activity induces new proteasome synthesis promoted by the transcription factor RPN4. This ensures that proteasome activity is matched to demand. This transcriptional feedback loop is conserved in mammals, but its molecular basis is not understood. Here, we report that nuclear factor erythroid-derived 2-related factor 1 (Nrf1), a transcription factor of the cap "n" collar basic leucine zipper family, but not the related Nrf2, is necessary for induced proteasome gene transcription in mouse embryonic fibroblasts (MEFs). Promoter-reporter assays revealed the importance of antioxidant response elements in Nrf1-mediated upregulation of proteasome subunit genes. Nrf1(-/-) MEFs were impaired in the recovery of proteasome activity after transient treatment with the covalent proteasome inhibitor YU101, and knockdown of Nrf1 in human cancer cells enhanced cell killing by YU101. Taken together, our results suggest that Nrf1-mediated proteasome homeostasis could be an attractive target for therapeutic intervention in cancer.
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The genotype-phenotype map uncovered known expression programs associated with perturbations, including upregulation of proteasomal subunits due to proteasome dysfunction, activation of NF-κB signaling upon loss of ESCRT proteins, and upregulation of cholesterol biosynthesis in response to defects in vesicular trafficking.
“This map uncovered many known expression programs associated with perturbations, including upregulation of proteasomal subunits due to proteasome dysfunction (Radhakrishnan et al., 2010), activation of NF-κB signaling upon loss of ESCRT proteins (Mamińska et al., 2016), and upregulation of cholesterol biosynthesis in response to defects in vesicular trafficking (Luo et al., 2020).”
From Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq (2022) · cites this paper as Radhakrishnan et al., 2010
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- Authors
- Radhakrishnan, S. K., Lee, C. S., Young, P., Beskow, A., Chan, J. Y., & Deshaies, R. J.
- Affiliations
- California Institute of Technology (US)
- University of California, Irvine (US)
- Stockholm University (SE)
- Corresponding author
- Deshaies, Raymond J.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 38
- Issue
- 1
- Pages
- 17-28
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2874685
- OpenAlex
- W2051641469
- Cited by
- 526
- References
- 50
- Citations by year
- 2026: 33 · 2025: 39 · 2024: 39 · 2023: 33 · 2022: 33 · 2021: 37 · 2020: 46 · 2019: 49 · 2018: 28 · 2017: 37 · 2016: 33 · 2015: 29 · 2014: 25 · 2013: 21 · 2012: 20
- FWCI
- 8.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA091907, CA091907, R56CA091907)
- National Institute of Neurological Disorders and Stroke (R01NS065223, NS065223)
- 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 › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- NRF1, proteasome inhibition, transcriptional feedback loop, antioxidant response element, mouse embryonic fibroblasts, cancer therapy targets
- MeSH terms
- Animals, Antineoplastic Agents, Antioxidants, Base Sequence, Cells, Cultured, Fibroblasts, Gene Expression Regulation, Humans, Leupeptins, Molecular Sequence Data, Oligopeptides, Saccharomyces cerevisiae, Cysteine Proteinase Inhibitors, Apoptosis, Mice, Knockout, Cell Line, Tumor, Proteasome Endopeptidase Complex, Nuclear Respiratory Factor 1, Mice, Proteasome Inhibitors
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