EIF4E 的非典型功能限制 ALDH1B1 活性并增加对铁死亡的易感性,Nature Communications

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EIF4E 的非典型功能限制 ALDH1B1 活性并增加对铁死亡的易感性
Nature Communications ( IF 14.7 ) Pub Date : 2022-10-23 , DOI: 10.1038/s41467-022-34096-w
Xin Chen _{1,

2,

3,

4} , Jun Huang ₅ , Chunhua Yu ₄ , Jiao Liu ₁ , Wanli Gao ₁ , Jingbo Li ₄ , Xinxin Song ₄ , Zhuan Zhou ₄ , Changfeng Li ₆ , Yangchun Xie ₇ , Guido Kroemer _{8,

9,

10} , Jinbao Liu _{2,

3} , Daolin Tang ₄ , Rui Kang ₄

Affiliation

DAMP Laboratory, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.
Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, China.
Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China.
Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800, Villejuif, France.
Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, 75015, Paris, France.

Ferroptosis 是一种脂质过氧化依赖性细胞死亡，正在成为癌症的治疗靶点。然而，在脂质过氧化产物的产生和解毒过程中铁死亡的机制仍然很不明确。在这里，我们报告了真核翻译起始因子 EIF4E 的意想不到的作用，它通过控制脂质过氧化作用作为铁死亡敏感性的决定因素。药物筛选确定 4EGI-1 和 4E1RCat（以前称为 EIF4E-EIF4G1 相互作用抑制剂）是铁死亡的强效抑制剂。遗传和功能研究表明，EIF4E（但不是 EIF4G1）以与翻译无关的方式促进铁死亡。使用质谱法和随后的蛋白质-蛋白质相互作用分析，我们将 EIF4E 鉴定为线粒体中 ALDH1B1 的内源性阻遏物。ALDH1B1 属于醛脱氢酶家族，可在高浓度下代谢醛底物 4-羟基壬醛 (4HNE)。超生理水平的 4HNE 引发铁死亡，而低浓度的 4HNE 通过激活 NOX1 通路增加细胞对经典铁死亡诱导剂的敏感性。因此，EIF4E 依赖性 ALDH1B1 抑制增强了铁死亡诱导剂在体外和体内的抗癌活性。我们的结果支持 EIF4E 在协调脂质过氧化以引发铁死亡中的关键功能。而低浓度的 4HNE 通过激活 NOX1 通路增加细胞对经典铁死亡诱导剂的敏感性。因此，EIF4E 依赖性 ALDH1B1 抑制增强了铁死亡诱导剂在体外和体内的抗癌活性。我们的结果支持 EIF4E 在协调脂质过氧化以引发铁死亡中的关键功能。而低浓度的 4HNE 通过激活 NOX1 通路增加细胞对经典铁死亡诱导剂的敏感性。因此，EIF4E 依赖性 ALDH1B1 抑制增强了铁死亡诱导剂在体外和体内的抗癌活性。我们的结果支持 EIF4E 在协调脂质过氧化以引发铁死亡中的关键功能。

"点击查看英文标题和摘要"

A noncanonical function of EIF4E limits ALDH1B1 activity and increases susceptibility to ferroptosis

Ferroptosis is a type of lipid peroxidation-dependent cell death that is emerging as a therapeutic target for cancer. However, the mechanisms of ferroptosis during the generation and detoxification of lipid peroxidation products remain rather poorly defined. Here, we report an unexpected role for the eukaryotic translation initiation factor EIF4E as a determinant of ferroptotic sensitivity by controlling lipid peroxidation. A drug screening identified 4EGI-1 and 4E1RCat (previously known as EIF4E-EIF4G1 interaction inhibitors) as powerful inhibitors of ferroptosis. Genetic and functional studies showed that EIF4E (but not EIF4G1) promotes ferroptosis in a translation-independent manner. Using mass spectrometry and subsequent protein-protein interaction analysis, we identified EIF4E as an endogenous repressor of ALDH1B1 in mitochondria. ALDH1B1 belongs to the family of aldehyde dehydrogenases and may metabolize the aldehyde substrate 4-hydroxynonenal (4HNE) at high concentrations. Supraphysiological levels of 4HNE triggered ferroptosis, while low concentrations of 4HNE increased the cell susceptibility to classical ferroptosis inducers by activating the NOX1 pathway. Accordingly, EIF4E-dependent ALDH1B1 inhibition enhanced the anticancer activity of ferroptosis inducers in vitro and in vivo. Our results support a key function of EIF4E in orchestrating lipid peroxidation to ignite ferroptosis.

更新日期：2022-10-23

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