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COVID19-NMR

COVID19-NMR

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Publications

DOI

RNA 2020 27(3):253-264. Online ahead of print.

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

A. Tidu, A. Janvier, L. Schaeffer, P. Sosnowski, L. Kuhn, P. Hammann, E. Westhof, G. Eriani, F. Martin

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.

Funded by


Goethe Corona Fonds

DFG

Volkswagen Stiftung

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Coordination

Prof. Dr. Harald Schwalbe (Coordinator)
Institut für Organische Chemie und Chemische Biologie
Zentrum für Biomolekulare Magnetische Resonanz

Johann Wolfgang Goethe-Universität
N160-3.13
Max-von-Laue-Strasse 7
D-60438 Frankfurt am Main

Contact us

++49 69 798 29737
schwalbe@nmr.uni-frankfurt.de

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