Cited by 134Selenium in Biological SystemsFerroptosis and cancer prognosisOrganoselenium and organotellurium chemistry

Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability

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Li, Zhipeng, Ferguson, Lucas, Deol, Kirandeep K., Roberts, Melissa A., Magtanong, Leslie, Hendricks, Joseph M., Mousa, Gergey Alzaem, Kilinc, Seda +7 more·2022·Nature Chemical Biology

Published 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.

    “LRP8 has been recently shown to affect ferroptosis by regulating the level of selenoprotein GPX4 in cancer cells (54–56).”

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  1. [39]Masiulis I, Quill TA, Burk RF & Herz J Differential functions of the Apoer2 intracellular domain in selenium uptake and cell signaling. Biol. Chem 390, 67– 73 (2009). 19007311 PMC2642607
  2. [50]Garzia A The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs. Nat. Commun 8, 16056 (2017). 28685749 PMC5504347

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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.
Venue
Nature Chemical Biology
Published
2022-05-30
Volume
18
Issue
7
Pages
751-761
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
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
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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