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Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability
Open accessPublished version of a preprint
Abstract
The selenoprotein glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid peroxides into nontoxic lipid alcohols. GPX4 has emerged as a promising therapeutic target for cancer treatment, but some cancer cells are resistant to ferroptosis triggered by GPX4 inhibition. Using a chemical-genetic screen, we identify LRP8 (also known as ApoER2) as a ferroptosis resistance factor that is upregulated in cancer. Loss of LRP8 decreases cellular selenium levels and the expression of a subset of selenoproteins. Counter to the canonical hierarchical selenoprotein regulatory program, GPX4 levels are strongly reduced due to impaired translation. Mechanistically, low selenium levels result in ribosome stalling at the inefficiently decoded GPX4 selenocysteine UGA codon, leading to ribosome collisions, early translation termination and proteasomal clearance of the N-terminal GPX4 fragment. These findings reveal rewiring of the selenoprotein hierarchy in cancer cells and identify ribosome stalling and collisions during GPX4 translation as ferroptosis vulnerabilities in cancer.
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“LRP8 has been recently shown to affect ferroptosis by regulating the level of selenoprotein GPX4 in cancer cells (54–56).”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [54]
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Cites
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Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691
Self-citationFerroptosis: mechanisms, biology and role in disease
Jiang, X., Stockwell, B. R., & Conrad, M. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00324-8 · Cited by 7,973
Regulation of Ferroptotic Cancer Cell Death by GPX4
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Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease
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Self-citationGenome-Wide Analysis in Vivo of Translation with Nucleotide Resolution Using Ribosome Profiling
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Self-citationThe CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis
Bersuker, K., Hendricks, J. M., Li, Z., Magtanong, L., Ford, B., Tang, P. H., Roberts, M. A., Tong, B., Maimone, T. J., Zoncu, R., et al. (2019) · Nature · doi:10.1038/s41586-019-1705-2 · Cited by 3,703
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The Cell Biology of Ferroptosis
Dixon, S. J., & Olzmann, J. A. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00703-5 · Cited by 1,596
Self-citationGPX4 in cell death, autophagy, and disease
Xie, Y., Kang, R., Klionsky, D. J., & Tang, D. (2023) · Autophagy · doi:10.1080/15548627.2023.2218764 · Cited by 682
Regulation of ferroptosis by lipid metabolism
Pope, L. E., & Dixon, S. J. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.05.003 · Cited by 615
Self-citationRibosome biogenesis in disease: new players and therapeutic targets
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A guideline on the molecular ecosystem regulating ferroptosis
Dai, E., Chen, X., Linkermann, A., Jiang, X., Kang, R., Kagan, V. E., Bayır, H., Yang, W. S., García‐Sáez, A. J., Ioannou, M. S., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01360-8 · Cited by 327
Metadata
- Authors
- Li, Z., Ferguson, L., Deol, K. K., Roberts, M. A., Magtanong, L., Hendricks, J. M., Mousa, G. A., Kilinc, S., Schaefer, K., Wells, J. A., Bassik, M. C., Goga, A., Dixon, S. J., Ingolia, N. T., & Olzmann, J. A.
- Affiliations
- University of California, Berkeley (US)
- Stanford University (US)
- University of California, San Francisco (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Corresponding author
- Olzmann, James A.
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2022-05-30
- Volume
- 18
- Issue
- 7
- Pages
- 751-761
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC9469796
- OpenAlex
- W4281664411
- Cited by
- 134
- References
- 69
- Citations by year
- 2026: 28 · 2025: 38 · 2024: 29 · 2023: 31 · 2022: 8
- FWCI
- 15.55
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Chemical Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- American Cancer Society (RSG-19-192-01)
- Melanoma Research Alliance (620458)
- U.S. Department of Health & Human Services | National Institutes of Health (R01GM112948, T32GM007232, F31DK121477, 2T32CA108462, R01CA223817, 1R01GM122923)
- Chan Zuckerberg Biohub, Miller Institute
- United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (W81XWH-18-1-0713)
- Mark Foundation
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Physical Sciences › Chemistry › Organic Chemistry › Organoselenium and organotellurium chemistry
- Keywords
- ribosome stalling, selenoprotein translation, GPX4, ferroptosis, ferroptosis resistance, LRP8, ApoER2, selenocysteine, UGA codon, selenium deficiency, cancer, chemical genetic screen, proteasomal degradation
- MeSH terms
- Ferroptosis, Phospholipid Hydroperoxide Glutathione Peroxidase, Ribosomes, Selenium, Selenoproteins
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