期刊
RNA
卷 27, 期 3, 页码 253-264出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1261/rna.078121.120
关键词
SARS-CoV-2; NSP1; SL1; 5'UTR; translation; ribosome
资金
- Agence Nationale pour la Recherche [ANR-17-CE12-0025-01, ANR-17-CE11-0024, ANR-20-COVI-0078]
- Fondation pour la Recherche Medicale (project CoronaIRES)
- Fondation Bettencourt Schueller
- University of Strasbourg
- Centre National de la Recherche Scientifique
- Agence Nationale de la Recherche (ANR) [ANR-20-COVI-0078, ANR-17-CE11-0024, ANR-17-CE12-0025] Funding Source: Agence Nationale de la Recherche (ANR)
This study reveals how SARS-CoV-2 coronavirus evades NSP1 inhibition through the SL1 RNA hairpin, promoting viral translation and necessary for translation of subgenomic RNAs in the late phase of infection. Therapeutic strategies targeting SL1 may affect viral translation at both early and late stages of infection, making SL1 a potential Achilles heel of the virus.
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.
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