p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates
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Significance: We have recently reported that glutamine synthetase (GS) is negatively regulated by glutamine through a feedback loop involving the E3 ubiquitin ligase CRL4 CRBN . However, the molecular events that take place at each step of the pathway are not well understood. Here, we show that valosin-containing protein (VCP)/p97, is required for GS degradation. It acts downstream of CRL4 CRBN . p97 extracts ubiquitylated GS subunits from the decamer so that they can be degraded by the proteasome. Interestingly, p97 is also required for immunomodulatory drug-induced degradation of all four known CRL4 CRBN neosubstrates, including Ikaros family zinc finger proteins 1 (IKZF1) and 3 (IKZF3), casein kinase 1α (CK1α), and the translation termination factor GSPT1, which accounts for antitumor activity of these drugs. Our findings could have important implications for patient responsiveness to cancer therapy with immunomodulatory drugs.
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PZ has no significant effect on expression of the CRBN native substrate glutamine synthetase and neosubstrates CK1α, IKZF1, and IKZF3.
“This is further supported by the observations that PZ could selectively induce Bcl-xl but not Bcl-2 poly-ubiquitination and had no significant effect on the expression of the CRBN native substrate, glutamine synthetase (GS)36, and its neosubstrates recruited by thalidomide and its analogues including CK1α37, IKZF1, and IKZF3 (ref. 38) (Supplementary Fig. 1 f, g).”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [37]
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“However, the molecular events that take place at each step of the Significance We have recently reported that glutamine synthetase (GS) is negatively regulated by glutamine through a feedback loop involving the E3 ubiquitin ligase CRL4CRBN.”
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- Authors
- Nguyen, T. V., Li, J., Lu, C.-C. (., Mamrosh, J. L., Lu, G., Cathers, B. E., & Deshaies, R. J.
- Affiliations
- California Institute of Technology (US)
- Celgene Corporation, San Diego, CA 92121;
- Corresponding author
- Deshaies, Raymond J.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-03-20
- Volume
- 114
- Issue
- 14
- Pages
- 3565-3571
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5389304
- OpenAlex
- W2599180871
- Cited by
- 85
- References
- 77
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 7 · 2023: 11 · 2022: 14 · 2021: 16 · 2020: 12 · 2019: 6 · 2018: 6 · 2017: 4
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- HHS | National Institutes of Health (NIH GM-065997)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- VCP/p97, glutamine synthetase, E3 ubiquitin ligase, protein degradation, proteasome, immunomodulators, IKZF1, IKZF3, CK1α, GSPT1, cancer therapy response
- MeSH terms
- Valosin Containing Protein, Glutamine, Glutamate-Ammonia Ligase, Humans, Peptide Hydrolases, Peptide Termination Factors, Signal Transduction, Ubiquitin-Protein Ligases, Casein Kinase I, Adaptor Proteins, Signal Transducing, Ikaros Transcription Factor, Ubiquitination, Proteolysis, MCF-7 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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