Société Française de Biochimie et Biologie Moléculaire


IBMC, Strasbourg "SARS-CoV-2 NSP1 induces mRNA cleavages on the ribosome"
Nucleic Acids Res. 2023 Jul 28,
Tardivat Y, Sosnowski P, Tidu A, Westhof E, Eriani G, Martin F


Yann Tardivat, aged 24, obtained a master's degree in virology from the University of Strasbourg in July 2022. Since September 2022, he has been pursuing a doctoral degree at the Institute of Molecular and Cellular Biology (IBMC) at the University of Strasbourg. He is working within the laboratory "Evolution of Translation Initiation Systems in Eukaryotes," under the supervision of Dr. Franck Martin and Dr. Gilbert Eriani. His project focuses on the study of viral and cellular translation during infection with the SARS-CoV-2 virus, specifically concentrating on the viral protein NSP1. This protein is involved in inhibiting cellular translation and degrading cellular mRNAs.



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Résumé de l'article

In severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the non-structural protein NSP1 inhibits translation of host mRNAs by binding to the mRNA entry channel of the ribosome and, together with the 5'-untranslated region (UTR) of the viral mRNAs, allows the evasion of that inhibition. Here, we show that NSP1 mediates endonucleolytic cleavages of both host and viral mRNAs in the 5'UTR, but with different cleavage patterns. The first pattern is observed in host mRNAs with cleavages interspersed regularly and close to the 5' cap (6-11 nt downstream of the cap). Those cleavage positions depend more on the position relative to the 5' cap than on the sequence itself. The second cleavage pattern occurs at high NSP1 concentrations and only in SARS-CoV-2 RNAs, with the cleavages clustered at positions 45, 46 and 49. Both patterns of cleavage occur with the mRNA and NSP1 bound to the ribosome, with the SL1 hairpin at the 5' end sufficient to protect from NSP1-mediated degradation at low NSP1 concentrations. We show further that the N-terminal domain of NSP1 is necessary and sufficient for efficient cleavage. We suggest that in the ribosome-bound NSP1 protein the catalytic residues of the N-terminal domain are unmasked by the remodelling of the α1- andα2-helices of the C-terminal domain.