Shared regulatory factors influencing mRNA translation rate and half-life in yeast

Extensive research has highlighted the role of codon composition in regulating co-translational mRNA decay. Translational efficiency is often measured using a codon usage metric like the codon adaptation index (CAI), while mRNA stability is assessed through sequence- and structure-dependent metrics such as codon stabilization coefficient and internal unstructured segments (IUS). However, the question remains whether sequence-dependent translation parameters can influence mRNA stability, or if stability-related parameters can, in turn, regulate mRNA translation and overall co-translational decay. Our approach integrates yeast mRNA sequence, structural, and ribosomal density (RD) data to explore the interconnected regulatory determinants that govern mRNA translation and degradation. Our findings offer new insights into how codon preferences and mRNA structuredness impact these processes, with CAI predominantly shaping translation rates and IUS affecting mRNA decay. Additionally, we observe that the impact of RD on co-translational mRNA decay is context-specific, depending on the dynamics of the primary regulators. These primary regulators are conserved across the genome and throughout evolution, emphasizing their importance in maintaining cellular function. We propose that optimizing both CAI and IUS is essential for improving mRNA-based drug delivery systems. A deeper understanding of the relationship between these factors could lead to more effective mRNA therapeutics.

大量研究已证实，密码子组成在调控共翻译mRNA降解（co-translational mRNA decay）过程中具有重要作用。翻译效率通常采用密码子使用类指标进行量化，例如密码子适应指数(CAI)；而mRNA稳定性则通过依赖于序列与结构的相关指标进行评估，如密码子稳定系数与内部非结构化区段(IUS)。然而，目前仍存在尚未厘清的科学问题：依赖于序列的翻译参数是否会影响mRNA稳定性，抑或是稳定性相关参数反过来能够调控mRNA翻译及整体共翻译mRNA降解过程？本研究整合了酵母的mRNA序列、结构数据与核糖体密度(RD)数据，以探究调控mRNA翻译与降解过程的相互关联的调控决定因子。本研究的发现为理解密码子偏好性与mRNA结构化程度如何影响上述过程提供了全新视角：密码子适应指数(CAI)主要主导翻译速率，而内部非结构化区段(IUS)则影响mRNA降解。此外，我们观察到核糖体密度(RD)对共翻译mRNA降解的影响具有情境特异性，其取决于核心调控因子的动态变化。这些核心调控因子在全基因组范围内及进化过程中均保守存在，凸显了它们在维持细胞功能中的重要性。我们提出，同时优化密码子适应指数(CAI)与内部非结构化区段(IUS)，对于改进基于mRNA的药物递送系统至关重要。对这些因素之间关联的更深入理解，有望助力开发更高效的mRNA疗法。