Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability
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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.
“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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- 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
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › 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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