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[Preprint]. 2024 May 2:arXiv:2405.01664v1.

Stress-induced Eukaryotic Translational Regulatory Mechanisms

Dilawar Ahmad Mir  1 , Zhengxin Ma  1 , Jordan Horrocks  1 , Aric N Rogers  1
Affiliations

Stress-induced Eukaryotic Translational Regulatory Mechanisms

Dilawar Ahmad Mir et al. ArXiv. .

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.

Keywords: Signaling; Stress; Translation Regulations Mechanisms; mRNA; mTOR.

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Conflict of interest statement

Conflict of Interest: None of the authors mentioned above have conflict of interest.

Figures

Figure 1:
Figure 1:. Eukaryotic Cap-Dependent Translation Initiation and its Key Regulatory Pathways:
Eukaryotic mRNAs comprise a 5′ m7G cap, which is bound by the eukaryotic initiation factor 4F complex (eIF4E, eIF4G, and eIF4A), and the ternary complex (eIF2-GTP-Met-tRNAi). Translation initiation starts with the assembly of the 43S preinitiation complex (PIC), consisting of the 40S ribosomal subunit, the ternary complex, and the initiation factors (eIF1, eIF1A, eIF3, eIF5). The PIC is recruited to the 5′ cap of the mRNA by the eIF4F complex and eIF4B. Binding of eIF4F to the 5′ cap and PABP to its poly(A) tail activates the mRNA. Successively, the 48S initiation complex is formed, and TC delivers Met-tRNA into the P-site of the ribosome. Before joining of the 60S ribosomal subunit to the PIC, all initiation factors are released from the 40S small ribosomal subunit. Finally, eIF5B unites the 40S and 60S ribosomal subunits to form the 80S initiation complex, and translation elongation begins.
Figure 2:
Figure 2:. Translation Regulation by eIF2α eukaryotic initiation factor 2 alpha is a pivotal factor in the initiation of translation.
When eIF2α undergoes phosphorylation, it impedes the assembly of the ternary complex (composed of eIF2, GTP, and initiator tRNA), thereby hindering translation initiation. The eIF2a kinases serve as rapid responders to disruptions in cellular equilibrium. This family comprises four members: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2a kinase (HRI), and general control nonderepressible 2 (GCN2). Each kinase is triggered by specific environmental or physiological stresses, reflecting their distinct regulatory pathways. PERK, PKR, HRI, and GCN2 kinases are activated by signals such as ER stress, viral infection, and other cellular stressors, leading to the phosphorylation of eIF2 α, a central component of the integrated stress response. Consequently, there is a global attenuation of cap-dependent translation.
Figure 3:
Figure 3:. Translation Regulation by mTOR, 4EBPS and MNK pathway:
The eIF4F complex plays a vital role in translation initiation, particularly in cap-dependent translation. It comprises three primary subunits: eIF4E: This protein binds to the 5’ cap structure of mRNA, serving as the cap-binding protein. eIF4A: An ATP-dependent RNA helicase, eIF4A unwinds the secondary structure of mRNA. eIF4G: Acting as a scaffold protein, eIF4G facilitates interactions between eIF4E, eIF4A, and mRNA. Additionally, there’s 4EBP (eIF4E-binding protein), which binds to eIF4E, preventing its interaction with eIF4G and thereby obstructing eIF4F complex formation. Under stress or starvation conditions, 4EBP binding to eIF4E inhibits translation initiation, while eIF2α phosphorylation reduces ternary complex formation. mTORC1 promotes the hyper-phosphorylation of 4EBP, preventing its inhibitory association with eIF4E, thus facilitating eIF4F complex assembly. Furthermore, mTOR enhances the phosphorylation of eIF4G and eIF4B, either directly or via S6 kinases. Given that eIF4E is the most limiting subunit of the eIF4F complex, its availability is crucial for recruiting eIF4A to mRNA. eIF4E activity is regulated by MAPK pathways, which directly phosphorylate eIF4E via the MNK protein kinases.
Figure 4:
Figure 4:. Schematic overview of the regulation of mRNA translation elongation.
Upon 80S complex formation, the ribosome is primed for translation elongation. eEF2 is regulated by the mTORC1 and MAP kinase signaling pathways by controlling eEF2K during stress. eEF2K is activated or inactivated by phosphorylation at Thr56 and Serine 398 residues by anabolic and mitogenic signaling agents (mTORC1 and MAP kinase pathway). Acidic conditions inhibit the phosphorylation reaction catalyzed by eEF2 kinase (eEF2K) and block translation.
Figure 5:
Figure 5:. Overview of translation regulation and stress granule formation:
Transcribed RNAs form nuclear messenger ribonucleoprotein particles (mRNPs). RNA-binding proteins linked with mRNA are shifted to the cytosol, where they govern cytoplasmic localization and translational proficiency of the mRNA. mRNA conversion into proteins activates the assembly of translation complexes, and when this process is stalled, the mRNPs accumulate as stress granules. Step 1: In normal translation, the eIF4F complex recruits the 43S ribosomal subunit. Upon recognition of the initiation codon by the anticodon of tRNAMet, eIF2-GTP is hydrolyzed, and eIF2-GDP is released, and early initiation factors are displaced by the 60S ribosomal subunit. Step 2: Under stress, mTORC1 promotes the hyper-phosphorylation of 4EBP, inhibiting the association of eIF4E with eIF4G and eIF4A to form the eIF4F complex properly, and blocking translation. Step 3: In stressed cells, phosphorylation of eIF2α by GCN2, HRI, dsRNA, PERK, and/or PKR converts eIF2 into a competitive antagonist of eIF2B, depleting the stores of eIF2/GTP/tRNAMet. This stops the exchange of GDP-GTP and the restoration of the 43S pre-initiation complex, inhibiting translation. Step 4: Upon eIF2α subunit blockage, elongating ribosomes ‘run-off’ the mRNA. Step 5: Following translation, mRNAs can quit translation and assemble a translationally repressed mRNP that can be either degraded or assembled into P bodies. mRNAs enclosed by P bodies can be subject to decapping and 5′−3′ degradation, or they can exchange P-body components for stress granule components to revert translation. Before re-entering translation, mRNAs should obtain extra translational components (eIF2, eIF3, and 40S subunits). Specific factors like mRNA binding proteins or the presence of a poly(A) tail might affect this process. So, mRNPs within stress granules can return to translation initiation again and enter polysomes or can be targeted for autophagy. Step 6: Translation inhibition, which causes the formation and aggregation of stress granules, is a consequence of the marked accumulation of untranslated mRNPs as a result of blocked initiation of translation, and the formation of stress granules themselves is not required for translation arrest. GTPase-activating protein-binding protein 1 (G3BP1) and T cell-restricted intracellular antigen 1 (TIA1) attach to the polysome-free mRNAs and build up to nucleate stress granule formation. Sodium selenite or hydrogen peroxide treatment (ROS generation) inhibits the functions of mTOR, resulting in stress granule formation. For granulation, G3BP1 must be dephosphorylated and demethylated. Poly(ADP)-ribosylated stimulates stress granule nucleation. Binding G3BP1 to cell cycle-associated protein 1 (CAPRIN1) encourages the formation of stress granules. Step 7: Aggregate large stress granules from smaller focal points. This approach includes retrograde microtubule-dependent trafficking mediated by dynein motors and histone deacetylase 6 (HDAC6) binding to G3BP1, microtubules, and polyubiquitin chains enriched in stress granules. Post-translational modifications of stress such as poly(ADP)-ribosylation and O-linked N-acetylglucosamination (O-GlcNAc) control the recruitment of different proteins. The O-GlcNAc-dependent recruitment of a receptor for activated RACK1 protein to stress granules causes RACK1-mediated pro-apoptotic signaling to be sequestered and inhibited. Neddylation, a post-translational modification, is necessary for the formation of stress granules by mediating the serine/arginine-rich splicing factor 3 (SRSF3) interactions with the eIF4F complex, N-acetylglucosamine, mRNP, messenger ribonucleoprotein.
Figure 6:
Figure 6:
mTORC1 activation initiates downstream catabolic processes and inhibits autophagy and lysosome biogenesis, among other macromolecules, while enhancing anabolic programs such as the production of proteins, lipids, and nucleotides. mTORC1 inhibition affects mRNA translation, splicing, and ribosome biogenesis. mTORC1 regulates its activity through its substrates 4EBP2 and S6K1.
Figure 7:
Figure 7:. Schematic representation of mTOR signaling to the translational machinery:
Rag GTPases, activated by amino acids, recruit mTORC1 to the surface of the lysosome, and the small GTPase Rheb activates mTORC1 in its GTP-bound state. The availability of amino acids controls the nucleotide state of the Rags; this process depends on the interplay between Ragulator and GATOR1. Ragulator serves as a lysosomal scaffold for RagA/B, and GATOR1 acts as a GTPase-activating protein (GAP) for RagA/B. GATOR1 is a critical negative regulator of the mTORC1 pathway. The GATOR2 complex acts in parallel to GATOR1 and is a key positive regulator of the mTORC1 pathway. The amino acid sensors Sestrin2 and SLC38A9 sense cytosolic leucine and putative lysosomal arginine, respectively, for the mTORC1 pathway. SAMTOR and CASTOR2 sense methionine and arginine, respectively, and starvation of these amino acids inhibits the mTORC1 pathway. In the absence of leucine, Sestrin2 interacts with GATOR2 and inhibits mTORC1 signaling, while SLC38A9 forms a supercomplex with Ragulator and is necessary for transmitting arginine, but not leucine, sufficiency to mTORC1. Following activation of the Ras/ERK pathway, S6K phosphorylates rpS6, eIF4B, PDCD4, and eEF2K, which are important regulators of translation. Low oxygen and energy conditions also diminish protein synthesis. Hypoxia requires the tuberous sclerosis complex (TSC) to downregulate S6K activity. In addition, translation initiation is inhibited under hypoxic conditions by the eIF2α-phosphorylating kinase PERK. Low cellular energy levels activate AMPK, which inhibits mTOR by stimulating TSC2 function.
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