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.

中文翻译：

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病毒蛋白 NSP1 作为核糖体看门人，关闭宿主翻译并促进 SARS-CoV-2 翻译

SARS-CoV-2 冠状病毒是导致 Covid-19 大流行的原因。在感染的早期阶段，单链阳性RNA基因组被翻译成非结构蛋白（NSP）。NSP1 是病毒感染过程中首先产生的蛋白质之一，它与宿主核糖体结合并阻断 mRNA 进入通道。这会触发细胞翻译的翻译抑制。尽管核糖体上存在 NSP1，但病毒翻译仍在继续。所谓的病毒逃避 NSP1 抑制的分子机制仍然难以捉摸。在这里，我们确认病毒翻译在 NSP1 存在的情况下得以维持。NSP1 抑制的逃避是由 SARS-CoV-2 5'UTR 中的顺式作用 RNA 发夹 SL1 介导的。NSP1 逃避可以通过 SL1 移植转移到报告基因转录本上。SL1 的顶端部分仅是病毒翻译所必需的。我们发现 NSP1 在病毒翻译过程中仍然与核糖体结合。我们认为 NSP1 和 SL1 之间的相互作用释放了 mRNA 调节通道，同时保持 NSP1 与核糖体结合。因此，NSP1 充当核糖体看门人，根据 SL1 5'UTR 发夹的存在来关闭宿主翻译或促进 SARS-CoV-2 翻译。SL1 也存在，并且是感染程序后期亚基因组 RNA 翻译所必需的。因此，针对 SL1 的治疗策略应该会影响感染早期和晚期的病毒翻译。因此，SL1 可能被视为该病毒真正的“致命弱点”。