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Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability.
Li, Zhipeng; Ferguson, Lucas; Deol, Kirandeep K; Roberts, Melissa A; Magtanong, Leslie; Hendricks, Joseph M; Mousa, Gergey Alzaem; Kilinc, Seda; Schaefer, Kaitlin; Wells, James A; Bassik, Michael C; Goga, Andrei; Dixon, Scott J; Ingolia, Nicholas T; Olzmann, James A.
Afiliação
  • Li Z; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • Ferguson L; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.
  • Deol KK; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • Roberts MA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • Magtanong L; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.
  • Hendricks JM; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • Mousa GA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.
  • Kilinc S; Department of Biology, Stanford University, Stanford, CA, USA.
  • Schaefer K; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • Wells JA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.
  • Bassik MC; Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA.
  • Goga A; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.
  • Dixon SJ; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
  • Ingolia NT; Department of Medicine, University of California, San Francisco, CA, USA.
  • Olzmann JA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
Nat Chem Biol ; 18(7): 751-761, 2022 07.
Article em En | MEDLINE | ID: mdl-35637349
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Selênio / Ferroptose Tipo de estudo: Prognostic_studies Idioma: En Revista: Nat Chem Biol Assunto da revista: BIOLOGIA / QUIMICA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
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PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Selênio / Ferroptose Tipo de estudo: Prognostic_studies Idioma: En Revista: Nat Chem Biol Assunto da revista: BIOLOGIA / QUIMICA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos