Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability

Zhipeng Li; Lucas Ferguson; Kirandeep K Deol; Melissa A Roberts; Leslie Magtanong; Joseph M Hendricks; Gergey Alzaem Mousa; Seda Kilinc; Kaitlin Schaefer; James A Wells; Michael C Bassik; Andrei Goga; Scott J Dixon; Nicholas T Ingolia; James A Olzmann

doi:10.1038/s41589-022-01033-3

Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability

Nat Chem Biol. 2022 Jul;18(7):751-761. doi: 10.1038/s41589-022-01033-3. Epub 2022 May 30.

Authors

Zhipeng Li^{1

2}, Lucas Ferguson¹, Kirandeep K Deol^{1

2}, Melissa A Roberts^{1

2}, Leslie Magtanong³, Joseph M Hendricks^{1

2}, Gergey Alzaem Mousa⁴, Seda Kilinc^{5

6

7}, Kaitlin Schaefer⁸, James A Wells^{8

9

10}, Michael C Bassik¹¹, Andrei Goga^{5

6

7}, Scott J Dixon³, Nicholas T Ingolia¹, James A Olzmann^{12

13

14

15}

Affiliations

¹ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
² Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.
³ Department of Biology, Stanford University, Stanford, CA, USA.
⁴ Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA.
⁵ Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.
⁶ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
⁷ Department of Medicine, University of California, San Francisco, CA, USA.
⁸ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
⁹ Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
¹⁰ Chan Zuckerberg Biohub, San Francisco, CA, USA.
¹¹ Department of Genetics, Stanford University, Stanford, CA, USA.
¹² Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. olzmann@berkeley.edu.
¹³ Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA. olzmann@berkeley.edu.
¹⁴ Chan Zuckerberg Biohub, San Francisco, CA, USA. olzmann@berkeley.edu.
¹⁵ Miller Institute for Basic Research in Science, University of California, Berkeley, Berkeley, CA, USA. olzmann@berkeley.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Ferroptosis*
Phospholipid Hydroperoxide Glutathione Peroxidase
Ribosomes / metabolism
Selenium* / metabolism
Selenium* / pharmacology
Selenoproteins / genetics

Substances

Selenoproteins
Phospholipid Hydroperoxide Glutathione Peroxidase
Selenium

Abstract

Publication types

MeSH terms

Substances

Grants and funding