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Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability. 2022

Zhipeng Li, and Lucas Ferguson, and Kirandeep K Deol, and Melissa A Roberts, and Leslie Magtanong, and Joseph M Hendricks, and Gergey Alzaem Mousa, and Seda Kilinc, and Kaitlin Schaefer, and James A Wells, and Michael C Bassik, and Andrei Goga, and Scott J Dixon, and Nicholas T Ingolia, and James A Olzmann
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.

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.

UI MeSH Term Description Entries
D000079403 Ferroptosis A form of REGULATED CELL DEATH initiated by oxidative perturbations of the intracellular microenvironment that is under constitutive control by glutathione peroxidase 4 and can be inhibited by iron chelators and lipophilic antioxidants. Oxytosis
D000080662 Phospholipid Hydroperoxide Glutathione Peroxidase A selenoenzyme that converts GLUTATHIONE plus FATTY ACID HYDROPEROXIDES to GLUTATHIONE DISULFIDE plus hydroxy fatty acids and water. GPX4 Phospholipid Hydroperoxide Glutathione Peroxidase,Glutathione Peroxidase 4,PH-GPeroxidase,PHGPx Enzyme,Phospholipid Hydroperoxide Glutathione Peroxidase GPX4,Phospholipid-Hydroperoxide Glutathione Peroxidase,Selenium-Dependent Glutathione Peroxidase Type-4,Glutathione Peroxidase, Phospholipid-Hydroperoxide,PH GPeroxidase,Selenium Dependent Glutathione Peroxidase Type 4
D012270 Ribosomes Multicomponent ribonucleoprotein structures found in the CYTOPLASM of all cells, and in MITOCHONDRIA, and PLASTIDS. They function in PROTEIN BIOSYNTHESIS via GENETIC TRANSLATION. Ribosome
D012643 Selenium An element with the atomic symbol Se, atomic number 34, and atomic weight 78.97. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of GLUTATHIONE PEROXIDASE. Selenium-80,Selenium 80
D051140 Selenoproteins Selenoproteins are proteins that specifically incorporate SELENOCYSTEINE into their amino acid chain. Most selenoproteins are enzymes with the selenocysteine residues being responsible for their catalytic functions. Selenoprotein,Selenoprotein P1

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