The Interaction Mechanism Between Translation Efficiency and mRNA Decay

The relationship between translation efficiency and mRNA decay is a complex process that governs gene expression. This interaction is fundamental to cellular homeostasis, regulating mRNA stability and ensuring that only correctly translated mRNAs are maintained. Multiple molecular mechanisms are involved in this interplay, including translation-coupled decay, the role of key proteins, and the impact of environmental factors. Understanding how translation efficiency and mRNA degradation intersect can provide deeper insights into gene expression regulation and the broader implications for cellular function and disease.

Translation Efficiency and Its Impact on mRNA Stability

Translation efficiency is directly linked to mRNA stability. mRNA that is translated efficiently tends to have a longer half-life compared to mRNA that is poorly translated. This phenomenon is critical in maintaining proper protein synthesis and cellular function. Several mechanisms explain how translation efficiency influences mRNA decay:

• Translation-Coupled Decay (TCD)

Translation-coupled decay (TCD) is a well-established mechanism where translation efficiency positively correlates with mRNA stability. mRNAs that are efficiently translated often have a higher codon adaptation index (CAI), which favors faster ribosomal movement along the transcript. These mRNAs tend to possess fewer internal untranslated regions (IUS), which are prone to forming secondary structures that could destabilize the mRNA. High translation efficiency results in a stable mRNA, while inefficiently translated mRNA, often characterized by a lower CAI and longer IUS, is more susceptible to decay.

• Translation-Dependent Decay (TDD)

In contrast to TCD, translation-dependent decay (TDD) occurs when translation events themselves promote the degradation of mRNA. Errors during translation, such as ribosomal stalling, could lead to the activation of degradation pathways. For example, ribosomal pausing or premature termination can induce mRNA decay, even in the absence of direct sequence-specific signals for degradation. This mechanism is particularly important in maintaining the fidelity of gene expression by ensuring that incorrectly translated mRNAs do not accumulate in the cell.

• Translation Suppression and mRNA Decay

Translation suppression, often mediated by microRNAs (miRNAs) or other regulatory factors, can also indirectly promote mRNA decay. miRNAs typically bind to the 3' untranslated region (UTR) of target mRNAs, preventing efficient translation initiation. The inhibition of translation can recruit mRNA decay factors, such as the CCR4-NOT complex, leading to accelerated degradation. In this way, translation repression serves as a precursor to mRNA decay, underlining the intricate regulation of mRNA stability.

The Interplay Between Translation Efficiency and mRNA Decay

The relationship between translation efficiency and mRNA decay is not purely linear, and in some cases, the two processes influence each other in a feedback loop. There are several important mechanisms through which translation and decay interact:

• Translation Inhibition and Decay Feedback Loop

Certain mRNAs may undergo translation inhibition during stress conditions or errors in translation initiation. This inhibition can trigger a decay response, forming a positive feedback loop where translation failure leads to the recruitment of mRNA decay factors. For example, ribosomal stalling or erroneous binding can trigger decay mechanisms like nonsense-mediated mRNA decay (NMD), which serves to eliminate potentially harmful or malfunctioning transcripts.

Fig 1 Model for biogenesis-coupled mRNA decay.¹

• Translation Elongation and Decay Antagonism

Conversely, translation elongation can exert a contrasting effect on mRNA stability. Prolonged translation elongation, especially in the presence of stressors or other cellular signals, can lead to ribosomal slippage or premature termination, both of which can result in mRNA decay. Ribosome collisions and stalling events are often linked to the activation of mRNA decay pathways such as no-go decay (NGD) or nonstop decay (NSD), which prevent the accumulation of incomplete or malformed proteins. Thus, while efficient translation can enhance mRNA stability, excessive elongation under stress can paradoxically accelerate degradation.

• Independent Regulation of Translation and Decay

Interestingly, some studies suggest that translation efficiency and mRNA decay can be regulated independently. Certain mRNAs may be subject to degradation even when translation is active. For instance, mRNAs with specific structural features or modified sequences might be recognized by decay factors even in the presence of ongoing translation. This indicates that other regulatory pathways, such as those involving RNA-binding proteins or stress-related factors, can override the effects of translation efficiency on mRNA stability.

Fig 2 Translation‐coupled mRNA quality control mechanisms.²

Key Proteins Involved in Translation Efficiency and mRNA Decay

Several proteins play a pivotal role in mediating the balance between translation efficiency and mRNA decay. These proteins either directly influence translation initiation or elongation, or they modulate the recruitment of decay factors to the mRNA.

• DEAD-box Protein Dhh1

Dhh1, a member of the DEAD-box family of RNA helicases, is a critical player in regulating translation efficiency and mRNA decay. Dhh1 can promote mRNA degradation by controlling the speed of translation. It is particularly involved in mRNAs that are translated inefficiently or stalled during elongation. When ribosomal movement slows, Dhh1 recognizes these mRNAs and facilitates their degradation. This mechanism ensures that inefficiently translated mRNAs do not accumulate and that resources are not wasted on incomplete translation.

• SMG-5/7 Complex and Nonsense-Mediated Decay (NMD)

The SMG-5 and SMG-7 proteins are essential for the nonsense-mediated mRNA decay (NMD) pathway, which targets mRNAs containing premature termination codons. NMD is a surveillance mechanism that eliminates faulty mRNA transcripts that could lead to the production of truncated and potentially harmful proteins. These proteins function by recognizing mRNAs with nonsense mutations and initiating their degradation, thus ensuring the accuracy of gene expression.

• Edc4 and mRNA Decapping

Edc4 is a key protein involved in the decapping of mRNA, a crucial step in mRNA decay. The decapping process removes the 7-methylguanosine cap from the 5' end of the mRNA, marking it for rapid degradation by exonucleases. Edc4 aids in the recruitment of the decapping complex, which facilitates the degradation of mRNA through both 5' to 3' exonuclease pathways and 3' to 5' exonuclease pathways. By controlling the rate of mRNA decapping, Edc4 indirectly regulates both the translation efficiency and stability of the transcript.

Environmental Factors Affecting Translation Efficiency and mRNA Decay

Translation efficiency and mRNA decay are not solely governed by intrinsic molecular mechanisms but can also be influenced by external environmental factors. Changes in cellular conditions can alter the stability and translation of mRNA.

• Nutritional Status and mRNA Localization

The nutritional state of a cell has a significant impact on translation efficiency and mRNA decay. For example, under nutrient-poor conditions such as glucose starvation, mRNA may be redistributed from the ribosome to P-bodies, specialized cytoplasmic foci involved in mRNA decay. In this context, reduced translation initiation leads to mRNA degradation, while certain mRNAs may be stored temporarily until conditions improve. This response helps the cell conserve energy and resources by limiting protein synthesis during unfavorable conditions.

• Temperature and Ionic Concentration

Temperature fluctuations and changes in ionic concentrations also affect mRNA stability and translation efficiency. Extreme temperatures or ionic stress can cause ribosomal stalling or misfolding of mRNAs, leading to the activation of decay pathways such as NGD or NSD. Furthermore, the secondary structure of mRNA can be influenced by temperature or ionic conditions, making certain regions more susceptible to ribosomal pausing and subsequent degradation.

Molecular Mechanisms of Translation Efficiency and mRNA Decay

Several molecular mechanisms contribute to the interplay between translation efficiency and mRNA decay. These mechanisms are crucial for maintaining the fidelity of gene expression and ensuring that only properly translated mRNAs are retained.

• Ribosome Binding and Disassociation

Ribosome dynamics, particularly ribosome binding and dissociation, play a significant role in mRNA decay. Errors in ribosome binding or the premature dissociation of the ribosome from the mRNA can lead to incomplete translation and trigger decay mechanisms. Ribosome stalling, often caused by translational errors or secondary structures within the mRNA, activates decay pathways that prevent the accumulation of defective mRNAs.

• tRNA and mRNA Decay

The role of tRNA in translation efficiency and mRNA decay is also noteworthy. Specific tRNAs can recruit the CCR4-NOT complex, which is involved in mRNA degradation. These tRNAs facilitate the degradation of mRNA by promoting its decapping and 3' end degradation, ultimately leading to the elimination of poorly translated or incomplete transcripts.

• Non-Coding Regions and Regulation of Translation and Decay

Non-coding regions of mRNA, such as the 3' UTR, play a critical role in regulating both translation efficiency and mRNA decay. These regions are often the sites of interactions with regulatory proteins, including microRNAs, that influence mRNA stability. By binding to these regions, microRNAs and other regulatory factors can modulate translation initiation and elongation, triggering mRNA decay when necessary.

Conclusion

The mechanisms regulating translation efficiency and mRNA decay are multifaceted and dynamic, with a variety of proteins, regulatory factors, and environmental conditions influencing mRNA stability. High translation efficiency generally leads to greater mRNA stability, while inefficient translation can trigger decay pathways. These processes are not only essential for maintaining gene expression but are also tightly linked to cellular responses to stress, disease, and environmental changes. Understanding the detailed mechanisms behind translation and decay provides valuable insights into cellular function and the regulation of gene expression.

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References

1. Höpfler, Markus, and Ramanujan S. Hegde. "Control of mRNA fate by its encoded nascent polypeptide." Molecular Cell 83.16 (2023): 2840-2855. Distributed under the Open Access license CC BY 4.0, without modification.
2. Monaghan, Laura, Dasa Longman, and Javier F. Cáceres. "Translation‐coupled mRNA quality control mechanisms." The EMBO Journal 42.19 (2023): e114378. Distributed under the Open Access license CC BY 3.0, without modification.