Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability,Nature Chemical Biology

当前位置： X-MOL 学术 › Nat. Chem. Biol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2022-05-30 , DOI: 10.1038/s41589-022-01033-3
Zhipeng Li _{1,

2} , Lucas Ferguson ₁ , Kirandeep K Deol _{1,

2} , Melissa A Roberts _{1,

2} , Leslie Magtanong ₃ , Joseph M Hendricks _{1,

2} , Gergey Alzaem Mousa ₄ , Seda Kilinc _{5,

6,

7} , Kaitlin Schaefer ₈ , James A Wells _{8,

9,

10} , Michael C Bassik ₁₁ , Andrei Goga _{5,

6,

7} , Scott J Dixon ₃ , Nicholas T Ingolia ₁ , James A Olzmann _{1,

2,

10,

12}

Affiliation

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA.
Department of Biology, Stanford University, Stanford, CA, USA.
Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA.
Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, CA, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
Chan Zuckerberg Biohub, San Francisco, CA, USA.
Department of Genetics, Stanford University, Stanford, CA, USA.
Miller Institute for Basic Research in Science, 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.

中文翻译：

硒蛋白翻译过程中核糖体停滞暴露了铁死亡的脆弱性

硒蛋白谷胱甘肽过氧化物酶 4 (GPX4) 通过将脂质过氧化物转化为无毒的脂质醇来预防铁死亡。 GPX4 已成为癌症治疗的一个有前途的治疗靶点，但一些癌细胞对 GPX4 抑制引发的铁死亡具有抵抗力。通过化学遗传筛选，我们发现 LRP8（也称为 ApoER2）是一种在癌症中表达上调的铁死亡抗性因子。 LRP8 的缺失会降低细胞硒水平和硒蛋白子集的表达。与典型的分级硒蛋白调节程序相反，GPX4 水平由于翻译受损而大大降低。从机制上讲，低硒水平会导致核糖体停滞在低效解码的 GPX4 硒代半胱氨酸 UGA 密码子处，从而导致核糖体碰撞、早期翻译终止和 N 端 GPX4 片段的蛋白酶体清除。这些发现揭示了癌细胞中硒蛋白层次结构的重新布线，并将 GPX4 翻译过程中的核糖体停滞和碰撞确定为癌症中铁死亡的脆弱性。

更新日期：2022-05-31

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11