Berlanga Juan José, Matamoros Tania, Pulido Miguel Rodríguez, Sáiz Margarita, Bayón Mercedes Núñez, Toribio René, Ventoso Iván
Centro de Biología Molecular Severo Ochoa (CSIC-UAM) and Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Centro de Biotecnología y Genómica de Plantas (CBGP), Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Campus de Montegancedo, Pozuelo de Alarcón, 28223 Madrid, Spain.
Nucleic Acids Res. 2025 Mar 20;53(6). doi: 10.1093/nar/gkaf261.
The nonstructural protein 1 (NSP1) of SARS-CoV-2 blocks the messenger RNA (mRNA) entry channel of the 40S ribosomal subunit, causing inhibition of translation initiation and subsequent degradation of host mRNAs. However, target mRNA specificity and how viral mRNAs escape NSP1-mediated degradation have not been clarified to date. Here we found that NSP1 acts as a translational switch capable of blocking or enhancing translation depending on how preinitiation complex, 43S-PIC, is recruited to the mRNA, whereas NSP1-mediated mRNA degradation mostly depends on codon usage bias. Thus, fast-translating mRNAs with optimal codon usage for human cells that preferentially recruit 43S-PIC by threading showed a dramatic sensitivity to NSP1. Translation of SARS-CoV-2 mRNAs escapes NSP1-mediated inhibition by a proper combination of suboptimal codon usage and slotting-prone 5' UTR. Thus, the prevalence of nonoptimal codons found in SARS-CoV-2 and other coronavirus genomes is favored by the distinctive effect that NSP1 plays on translation and mRNA stability.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的非结构蛋白1（NSP1）阻断40S核糖体亚基的信使核糖核酸（mRNA）进入通道，导致翻译起始受到抑制以及宿主mRNA随后被降解。然而，靶mRNA的特异性以及病毒mRNA如何逃避NSP1介导的降解，迄今为止尚未阐明。在此，我们发现NSP1作为一种翻译开关，根据起始前复合物43S-PIC如何被招募到mRNA上，能够阻断或增强翻译，而NSP1介导的mRNA降解主要取决于密码子使用偏好。因此，对于人类细胞而言，具有最佳密码子使用且通过穿线优先招募43S-PIC的快速翻译mRNA对NSP1表现出显著的敏感性。SARS-CoV-2 mRNA的翻译通过次优密码子使用和易于插入的5'非翻译区（UTR）的适当组合，逃避了NSP1介导的抑制。因此，在SARS-CoV-2和其他冠状病毒基因组中发现的非最佳密码子的普遍存在，受到NSP1对翻译和mRNA稳定性所起的独特作用的影响。
