美国杜克大学董欣年课题组发现，无处不在的下游RNA发夹动态决定起始密码子的选择。这一研究成果于2023年9月6日在线发表在国际学术期刊《自然》上。

通过整合拟南芥模式诱导免疫过程中整个转录组的翻译和结构分析，研究人员发现免疫诱导翻译的转录本富含上游开放阅读框（uORF）。在没有感染的情况下，这些uORF会由于紧靠上游起始密码子（uAUG）下游的发夹而被选择性翻译，这可能是通过减缓扫描起始前复合体的速度并使其参与翻译。利用深度学习建模为uAUG下游这些可识别的双链RNA结构（被称之为uAUG-ds）负责uAUG的选择性翻译提供了无偏支持，并允许预测和合理设计可翻译的uAUG-ds。研究人员发现uAUG-ds介导的调控可以推广到人类细胞。

此外，uAUG-ds介导的起始密码子选择是动态调节的。植物受到免疫挑战后，与酵母中的Ded1p和人类中的DDX3X同源的诱导RNA螺旋酶会分解这些结构，使核糖体绕过uAUG翻译下游防御蛋白。这项研究表明，mRNA结构能动态调节起始密码子的选择。这种RNA结构特征的普遍性和跨物种RNA螺旋酶的保守性表明，mRNA结构重塑是翻译重编程的一个普遍特征。

据介绍，翻译重编程使生物能够适应不断变化的条件。mRNA中普遍存在的uAUG通过提供可供选择的翻译起始位点在调节翻译方面发挥着至关重要的作用。然而，是什么决定了翻译在不同条件下的选择性启动仍不清楚。

附：英文原文

Title: Pervasive downstream RNA hairpins dynamically dictate start-codon selection

Author: Xiang, Yezi, Huang, Wenze, Tan, Lianmei, Chen, Tianyuan, He, Yang, Irving, Patrick S., Weeks, Kevin M., Zhang, Qiangfeng Cliff, Dong, Xinnian

Issue&Volume: 2023-09-06

Abstract: Translational reprogramming allows organisms to adapt to changing conditions. Upstream start codons (uAUGs), which are prevalently present in mRNAs, have crucial roles in regulating translation by providing alternative translation start sites1–4. However, what determines this selective initiation of translation between conditions remains unclear. Here, by integrating transcriptome-wide translational and structural analyses during pattern-triggered immunity in Arabidopsis, we found that transcripts with immune-induced translation are enriched with upstream open reading frames (uORFs). Without infection, these uORFs are selectively translated owing to hairpins immediately downstream of uAUGs, presumably by slowing and engaging the scanning preinitiation complex. Modelling using deep learning provides unbiased support for these recognizable double-stranded RNA structures downstream of uAUGs (which we term uAUG-ds) being responsible for the selective translation of uAUGs, and allows the prediction and rational design of translating uAUG-ds. We found that uAUG-ds-mediated regulation can be generalized to human cells. Moreover, uAUG-ds-mediated start-codon selection is dynamically regulated. After immune challenge in plants, induced RNA helicases that are homologous to Ded1p in yeast and DDX3X in humans resolve these structures, allowing ribosomes to bypass uAUGs to translate downstream defence proteins. This study shows that mRNA structures dynamically regulate start-codon selection. The prevalence of this RNA structural feature and the conservation of RNA helicases across kingdoms suggest that mRNA structural remodelling is a general feature of translational reprogramming. Double-stranded RNA structures downstream of start codons play a role in translation initiation by regulating start-codon selection in plant immune responses, and also contribute to translational reprogramming in mammalian systems.

DOI: 10.1038/s41586-023-06500-y

Source: https://www.nature.com/articles/s41586-023-06500-y