[论文解读] Stress-induced Eukaryotic Translational Regulatory Mechanisms

Dilawar Ahmad Mir, Zhengxin Ma+2 more|PubMed|May 2, 2024

RNA modifications and cancer参考文献 276被引用 7

一句话总结

这是对真核细胞在压力下如何调控翻译的综述，涵盖 mRNA 特异性与全局控制、起始因子，以及在不利条件下塑造蛋白质合成的信号通路。

ABSTRACT

The eukaryotic protein synthesis process entails intricate stages governed by diverse mechanisms to tightly regulate translation. Translational regulation during stress is pivotal for maintaining cellular homeostasis, ensuring the accurate expression of essential proteins crucial for survival. This selective translational control mechanism is integral to cellular adaptation and resilience under adverse conditions. This review manuscript explores various mechanisms involved in selective translational regulation, focusing on mRNA-specific and global regulatory processes. Key aspects of translational control include translation initiation, which is often a rate-limiting step, and involves the formation of the eIF4F complex and recruitment of mRNA to ribosomes. Regulation of translation initiation factors, such as eIF4E, eIF4E2, and eIF2, through phosphorylation and interactions with binding proteins, modulates translation efficiency under stress conditions. This review also highlights the control of translation initiation through factors like the eIF4F complex and the ternary complex and also underscores the importance of eIF2α phosphorylation in stress granule formation and cellular stress responses. Additionally, the impact of amino acid deprivation, mTOR signaling, and ribosome biogenesis on translation regulation and cellular adaptation to stress is also discussed. Understanding the intricate mechanisms of translational regulation during stress provides insights into cellular adaptation mechanisms and potential therapeutic targets for various diseases, offering valuable avenues for addressing conditions associated with dysregulated protein synthesis.

研究动机与目标

• 在细胞应激期间，研究翻译在 mRNA 级别上的选择性调控。
• 概述在应激下改变整体蛋白质合成的全球调控机制。
• 突出关键的起始因子及其在应激反应中的磷酸化/相互作用动态。
• 讨论应激颗粒、氨基酸感知和核糖体生物发生在应激适应中的作用。

提出的方法

• 综合现有关于应激期间真核翻译控制的文献。
• 探讨翻译起始的调控，包括 eIF4F 复合体的形成和mRNA向核糖体的招募。
• 回顾通过磷酸化和结合相互作用对起始因子（如 eIF4E、eIF4E2、eIF2）进行的调控。
• 考察 eIF2α 磷酸化在应激颗粒形成和细胞应激反应中的作用。
• 考虑氨基酸匮乏、mTOR 信号传导和核糖体生物发生对翻译调控的影响。

实验结果

研究问题

• RQ1 在细胞应激期间，哪些机制调控特定 mRNA 的选择性翻译？
• RQ2 起始因子 eIF4F、eIF4E/eIF4E2 和 eIF2 在应激条件下如何调控翻译？
• RQ3 eIF2α 磷酸化在应激颗粒形成和细胞应激反应中的作用是什么？
• RQ4 营养感知（氨基酸匮乏）和 mTOR 信号传导如何影响应激中的翻译控制？
• RQ5 核糖体生物发生和全局翻译如何适应压力环境？

主要发现

• 综述概述了应激所激活的既有 mRNA 特异性又有全球性翻译控制机制。
• 翻译起始是被高度调控的关键步骤，eIF4F 复合体在将 mRNA 招募到核糖体中的作用。
• 起始因子如 eIF4E、eIF4E2、eIF2 的磷酸化和相互作用在应激下调控翻译效率。
• eIF2α 磷酸化与应激颗粒的形成以及更广泛的应激反应相关。
• 氨基酸感知、mTOR 信号传导和核糖体生物发生是应对应激的翻译适应性调控的重要因素。