近日，以色列魏茨曼科学研究所教授Noam Stern-Ginossar及其课题组探明了N1-甲基伪尿嘧啶直接调节翻译动力学。该研究于2026年1月14日发表于国际一流学术期刊《自然》杂志上。

在这里，课题组研究人员在亚密码子分辨率上进行核糖体分析，以表明m¹Ψ增加了合成mRNA上的核糖体密度，导致更高的蛋白质产量，而不依赖于先天免疫激活或eIF2α磷酸化。研究小组发现m¹Ψ直接减缓核糖体在定义序列背景下的运动，同时促进翻译起始。以低温电子显微镜为主题的结构研究揭示m¹Ψ改变核糖体解码中心内的相互作用，为减缓延伸提供了机制基础。

此外，通过引入同义重编码，破坏修饰介导的延伸变化，课题组研究人员发现m¹Ψ-dependent蛋白质输出的增强是由密码子组成调节的，并且m¹Ψ对含有非最佳密码子的mRNA的影响最大，而尿苷位于摆动位置。总之，这些发现表明m¹Ψ直接调节翻译动态，从而增加特定序列背景下合成mRNA的蛋白质产量。

据悉，针对SARS-CoV-2的mRNA疫苗的巨大成功凸显了合成mRNA作为一种变革性生物医学技术的潜力。这种方法的一个关键特征是加入了修饰的核苷N1-甲基假二吡啶（m¹Ψ），它可以增强抗原表达，同时降低免疫原性。然而，对m1Ψ如何影响翻译的全面理解仍然不完整。

附：英文原文

Title: N1-Methylpseudouridine directly modulates translation dynamics

Author: Rozman, Batsheva, Broennimann, Karin, Rajan, K. Shanmugha, Nachshon, Aharon, Saha, Chiranjeet, Arazi, Tamar, Mohan, Vishnu, Geiger, Tamar, Wollner, Clayton J., Richner, Justin M., Westhof, Eric, Yonath, Ada, Bashan, Anat, Stern-Ginossar, Noam

Issue&Volume: 2026-01-14

Abstract: The considerable success of mRNA vaccines against SARS-CoV-2 has underscored the potential of synthetic mRNA as a transformative biomedical technology1. A critical feature of this approach is the incorporation of the modified nucleoside N1-methylpseudouridine (m1Ψ), which enhances antigen expression while reducing immunogenicity2,3,4,5. However, a comprehensive understanding of how m1Ψ influences translation remains incomplete. Here we use ribosome profiling at the subcodon resolution to show that m1Ψ increases ribosome density on synthetic mRNAs, leading to higher protein production independent of innate immune activation or eIF2α phosphorylation. We find that m1Ψ directly slows ribosome movement in defined sequence contexts while simultaneously promoting translation initiation. Structural studies using cryo-electron microscopy reveal that m1Ψ alters interactions within the ribosomal decoding centre, providing a mechanistic basis for slowed elongation. Furthermore, by introducing synonymous recoding that disrupts the modification-mediated changes in elongation, we show that the m1Ψ-dependent enhancement of protein output is modulated by codon composition, and that m1Ψ impact is strongest in mRNAs containing non-optimal codons with uridines at the wobble position. Together, these findings demonstrate that m1Ψ directly modulates translation dynamics, thereby increasing protein yield from synthetic mRNAs in specific sequence contexts.

DOI: 10.1038/s41586-025-09945-5

Source: https://www.nature.com/articles/s41586-025-09945-5