[Paper Review] Stress-induced Eukaryotic Translational Regulatory Mechanisms

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

RNA modifications and cancer276 references7 citations

TL;DR

This is a review of how eukaryotic cells regulate translation under stress, covering mRNA-specific and global control, initiation factors, and signaling pathways that shape protein synthesis during adverse conditions.

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.

Motivation & Objective

• Examine how translation is selectively regulated at the mRNA level during cellular stress.
• Summarize the global regulatory mechanisms that alter overall protein synthesis under stress.
• Highlight key initiation factors and their phosphorylation/interaction dynamics in stress responses.
• Discuss the roles of stress granules, amino acid sensing, and ribosome biogenesis in stress adaptation.

Proposed method

• Synthesizes existing literature on eukaryotic translational control during stress.
• Explores regulation of translation initiation, including eIF4F complex formation and recruitment of mRNA to ribosomes.
• Reviews modulation of initiation factors (eIF4E, eIF4E2, eIF2) via phosphorylation and binding interactions.
• Examines the role of eIF2α phosphorylation in stress granule formation and cellular stress responses.
• Considers the impact of amino acid deprivation, mTOR signaling, and ribosome biogenesis on translation regulation.

Experimental results

Research questions

• RQ1 What mechanisms govern selective translation of specific mRNAs during cellular stress?
• RQ2 How do initiation factors eIF4F, eIF4E/eIF4E2, and eIF2 regulate translation under stress conditions?
• RQ3 What is the role of eIF2α phosphorylation in stress granule formation and cellular stress responses?
• RQ4 How do nutrient sensing (amino acid deprivation) and mTOR signaling influence translational control during stress?
• RQ5 How do ribosome biogenesis and global translation adapt to stressful environments?

Key findings

• The review outlines both mRNA-specific and global translational control mechanisms activated by stress.
• Translation initiation is a central regulated step, with eIF4F complex involvement in recruiting mRNA to ribosomes.
• Phosphorylation and interactions of initiation factors like eIF4E, eIF4E2, and eIF2 modulate translation efficiency under stress.
• eIF2α phosphorylation is linked to stress granule formation and broader stress responses.
• Amino acid sensing, mTOR signaling, and ribosome biogenesis are important contributors to adaptive translation control under stress.