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降解过程中的关键作用。翻译效率通常可通过密码子使用相关度量指标（如密码子适应指数（codon adaptation index, CAI））进行评估，而mRNA稳定性则通过序列与结构依赖的度量指标（如密码子稳定系数与内部非结构化区域（internal unstructured segments, IUS））进行量化。然而目前仍存在一个核心问题：依赖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可反过来调控mRNA翻译与整体共翻译降解过程？本研究整合了酵母的mRNA序列、结构及核糖体密度（ribosomal density, RD）数据，以探索调控mRNA翻译与降解的相互关联的调控决定因素。本研究结果为密码子偏好性与mRNA结构化程度如何影响这两类过程提供了新视角：密码子适应指数主要调控翻译速率，而内部非结构化区域则对mRNA降解产生影响。此外，本研究还观察到核糖体密度对共翻译mRNA降解的影响具有情境特异性，其作用依赖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，凸显了其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与内部非结构化区域，对于优化基于mRNA的药物递送系统至关重要。深入解析这些因素间的关联，有望推动更高效的mRNA疗法的开发。