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The viral protein NSP1 acts as a ribosome gatekeeper for shutting down host translation and fostering SARS-CoV-2 translation

机译:病毒蛋白NSP1充当核糖体的守护者用于关闭主机翻译和培养SARS-COV-2翻译

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摘要

SARS-CoV-2 coronavirus is responsible for the Covid-19 pandemic. In the early phase of infection, the single-strand positive RNA genome is translated into nonstructural 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. Despite 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 and we show that the evasion to NSP1-inhibition is mediated by the cis-acting RNA hairpin SL1 in the 5′UTR of SARS-CoV-2. Only the apical part of SL1 is required for viral translation. We further 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 and fostering SARS-CoV-2 translation in the presence of the SL1 5′UTR hairpin. SL1 is also present and necessary for translation of subgenomic 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 “Achilles heel” of the virus.
机译:SARS-COV-2冠状病毒负责Covid-19大流行。在感染的早期阶段,单链阳性RNA基因组转化为非结构蛋白(NSP)。在病毒感染期间产生的第一蛋白质中的一种,NSP1与宿主核糖体结合并阻断mRNA进入通道。这种触发翻译抑制细胞翻译。尽管存在NSP1对核糖体上的NSP1,但是病毒翻译需要进行。所谓的病毒缺陷对NSP1抑制的分子机制仍然是难以捉摸的。在这里,我们确认在NSP1的存在存在下维持病毒翻译,并且我们表明,在SARS-COV-2的5'UTR中,通过CIS作用RNA毛发蛋白SL1介导的厌恶对NSP1抑制。只需要SL1的顶端部分进行病毒翻译。我们进一步表明,在病毒翻译期间NSP1仍然在核糖体上束缚。我们建议NSP1和SL1之间的相互作用使MRNA住宿通道释放,同时保持与核糖体结合的NSP1。因此,NSP1充当核糖体网守,在SL1 5'UTR发夹的情况下关闭主机翻译和培育SARS-COV-2翻译。 SL1也存在并在传染计划后期翻译亚基MRNA翻译。因此,靶向SL1的治疗策略应在感染的早期和晚期阶段影响病毒翻译。因此,SL1可能被视为病毒的真正“Achilles脚跟”。

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