Tidu Antonin, Janvier Aurelie, Schaeffer Laure, Sosnowski Piotr, Kuhn Lauriane, Hammann Philippe, Westhof Eric, Eriani Gilbert, Martin Franck
Institut de Biologie Moleculaire et Cellulaire, Architecture et Reactivite de l ARN CNRS UPR9002, Universite de Strasbourg, 2, allee Konrad Roentgen, F-67084 Strasbourg (France).
Institut de Biologie Moleculaire et Cellulaire, Architecture et Reactivite de l ARN CNRS UPR9002, Universite de Strasbourg, 2, allee Konrad Roentgen F-67084 Strasbourg (France).
RNA. 2020 Dec 2;27(3):253-64. doi: 10.1261/rna.078121.120.
SARS-CoV-2 coronavirus is responsible for Covid-19 pandemic. In the early phase of infection, the single-strand positive RNA genome is translated into non-structural proteins (NSP). One of the first proteins produced during viral infection, NSP1, binds to the host ribosome and blocks the mRNA entry channel. This triggers translation inhibition of cellular translation. In spite of the presence of NSP1 on the ribosome, viral translation proceeds however. The molecular mechanism of the so-called viral evasion to NSP1 inhibition remains elusive. Here, we confirm that viral translation is maintained in the presence of NSP1. The evasion to NSP1-inhibition is mediated by the cis-acting RNA hairpin SL1 in the 5'UTR of SARS-CoV-2. NSP1-evasion can be transferred on a reporter transcript by SL1 transplantation. The apical part of SL1 is only required for viral translation. We show that NSP1 remains bound on the ribosome during viral translation. We suggest that the interaction between NSP1 and SL1 frees the mRNA accommodation channel while maintaining NSP1 bound to the ribosome. Thus, NSP1 acts as a ribosome gatekeeper, shutting down host translation or fostering SARS-CoV-2 translation depending on the presence of the SL1 5'UTR hairpin. SL1 is also present and necessary for translation of sub-genomic RNAs in the late phase of the infectious program. Consequently, therapeutic strategies targeting SL1 should affect viral translation at early and late stages of infection. Therefore, SL1 might be seen as a genuine 'Achille heel' of the virus.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引发了新冠疫情。在感染的早期阶段，单链阳性RNA基因组被翻译为非结构蛋白（NSP）。NSP1是病毒感染过程中最早产生的蛋白之一，它与宿主核糖体结合并阻断mRNA进入通道，从而引发细胞翻译的抑制。尽管核糖体上存在NSP1，但病毒翻译仍在继续。这种所谓的病毒逃避NSP1抑制的分子机制仍然不清楚。在这里，我们证实了在存在NSP1的情况下病毒翻译仍得以维持。对NSP1抑制的逃避是由SARS-CoV-2 5'非翻译区（UTR）中的顺式作用RNA发夹结构SL1介导的。通过SL1移植，NSP1逃避作用可以转移到报告转录本上。SL1的顶端部分仅对病毒翻译是必需的。我们表明，在病毒翻译过程中NSP1仍然与核糖体结合。我们认为，NSP1与SL1之间的相互作用在使NSP1与核糖体结合的同时释放了mRNA容纳通道。因此，NSP1充当核糖体的守门人，根据SL1 5'UTR发夹结构的存在与否，关闭宿主翻译或促进SARS-CoV-2翻译。SL1在感染程序后期亚基因组RNA的翻译中也存在且是必需的。因此，针对SL1的治疗策略应在感染的早期和晚期影响病毒翻译。所以说，SL1可能被视为该病毒真正的“阿喀琉斯之踵”。
