Intrinsic RNA-Binding Preferences of Eukaryotic Translation Initiation Factor eIF4G Contribute to Competitive Discrimination of Different mRNAs

Translational control of gene expression plays essential roles in cellular stress responses and organismal development by enabling rapid, selective, and localized control of protein production. Translational regulation depends on context-dependent differences in the translational efficiencies of mRNAs, but the key mRNA features that distinguish efficiently translated mRNAs are largely unknown. Here we comprehensively determined the RNA-binding preferences of the initiation factor eIF4G to assess whether core translation initiation factors have intrinsic sequence preferences that contribute to preferential translation of specific mRNAs. We identified a simple sequence motif—oligo-uridine—that mediates high-affinity binding to eIF4G. Oligo(U) motifs occur naturally in the transcript leaders of hundreds of yeast genes and are conserved between yeast species. Notably, mRNAs containing oligo(U) motifs resist translational repression upon depletion of eIF4G, demonstrating the impact of these motifs in vivo. Together, our data suggest a mechanism for selective translational control mediated by core initiation factors.

基因表达的翻译调控（Translational control of gene expression）通过介导蛋白质合成的快速、选择性与本地化调控，在细胞应激反应及个体发育中发挥不可或缺的核心作用。翻译调控依赖于信使RNA（mRNA）翻译效率的情境依赖差异，但目前学界对区分高效翻译信使RNA的关键mRNA特征仍知之甚少。本研究全面测定了翻译起始因子eIF4G的RNA结合偏好性，旨在探究核心翻译起始因子是否存在内在序列偏好性，进而介导特定信使RNA的选择性翻译。本研究鉴定出一种简单的序列基序——寡聚尿苷酸（oligo-uridine）——可介导与eIF4G的高亲和力结合。寡聚尿苷酸（Oligo(U)）基序天然存在于数百种酵母基因的转录前导区中，且在不同酵母物种间具有序列保守性。值得注意的是，携带寡聚尿苷酸基序的信使RNA在eIF4G表达敲低后可抵抗翻译抑制，证实了该基序在体内的调控作用。综上，本研究数据揭示了一种由核心翻译起始因子介导的选择性翻译调控机制。