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真核起始因子 3 mRNA 选择性分析揭示 eIF3k 作为一种与癌症相关的核糖体含量调控因子。

eIF3 mRNA selectivity profiling reveals eIF3k as a cancer-relevant regulator of ribosome content.

机构信息

State Key Laboratory of Stress Biology and Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.

Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel.

出版信息

EMBO J. 2023 Jun 15;42(12):e112362. doi: 10.15252/embj.2022112362. Epub 2023 May 8.

DOI:10.15252/embj.2022112362
PMID:37155573
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10267700/
Abstract

eIF3, whose subunits are frequently overexpressed in cancer, regulates mRNA translation from initiation to termination, but mRNA-selective functions of individual subunits remain poorly defined. Using multiomic profiling upon acute depletion of eIF3 subunits, we observed that while eIF3a, b, e, and f markedly differed in their impact on eIF3 holo-complex formation and translation, they were each required for cancer cell proliferation and tumor growth. Remarkably, eIF3k showed the opposite pattern with depletion promoting global translation, cell proliferation, tumor growth, and stress resistance through repressing the synthesis of ribosomal proteins, especially RPS15A. Whereas ectopic expression of RPS15A mimicked the anabolic effects of eIF3k depletion, disruption of eIF3 binding to the 5'-UTR of RSP15A mRNA negated them. eIF3k and eIF3l are selectively downregulated in response to endoplasmic reticulum and oxidative stress. Supported by mathematical modeling, our data uncover eIF3k-l as a mRNA-specific module which, through controlling RPS15A translation, serves as a rheostat of ribosome content, possibly to secure spare translational capacity that can be mobilized during stress.

摘要

真核翻译起始因子 3（eIF3）的亚基在癌症中经常过表达，它调节从起始到终止的 mRNA 翻译，但单个亚基的 mRNA 选择性功能仍未得到明确界定。通过急性耗尽 eIF3 亚基的多组学分析，我们观察到 eIF3a、b、e 和 f 在其对 eIF3 全复合物形成和翻译的影响方面显著不同，但它们对于癌细胞增殖和肿瘤生长都是必需的。值得注意的是，eIF3k 表现出相反的模式，通过抑制核糖体蛋白（尤其是 RPS15A）的合成来促进整体翻译、细胞增殖、肿瘤生长和应激抵抗。而 RPS15A 的异位表达模拟了 eIF3k 耗尽的合成代谢效应，而破坏 eIF3 与 RSP15A mRNA 的 5'-UTR 的结合则消除了这些效应。eIF3k 和 eIF3l 会响应内质网和氧化应激而被选择性地下调。受数学模型的支持，我们的数据揭示了 eIF3k-l 作为一个 mRNA 特异性模块，通过控制 RPS15A 的翻译，作为核糖体含量的变阻器，可能在应激期间确保可动员的备用翻译能力。

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