SARS-CoV-2 protein NSP2 enhances microRNA-mediated translational repression

Naeli, P.; Zhang, X.; Harris Snell, P.; Chatterjee, S.; Kamran, M.; Ladak, R. J.; Orr, N.; Duchaine, T.; Sonenberg, N.; Jafarnejad, S. M.

doi:10.1101/2023.01.01.522328

bioRxiv · 10.1101/2023.01.01.522328

SARS-CoV-2 protein NSP2 enhances microRNA-mediated translational repression

Naeli, P.·Zhang, X.·Harris Snell, P.·Chatterjee, S.·Kamran, M.·Ladak, R. J.·Orr, N.·Duchaine, T.·Sonenberg, N.·Jafarnejad, S. M.

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Abstract

microRNAs (miRNAs) inhibit mRNA translation initiation by recruiting the GIGYF2/4EHP translation repressor complex to the mRNA 5 cap structure. Viruses utilise miRNAs to impair the host antiviral immune system and facilitate viral infection by expressing their own miRNAs or co-opting cellular miRNAs. We recently reported that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encoded non-structural protein 2 (NSP2) interacts with GIGYF2. This interaction is critical for blocking translation of the Ifn1-b mRNA that encodes the cytokine Interferon-{beta}, and thereby impairs the host antiviral immune response. However, it is not known whether NSP2 also affects miRNA-mediated silencing. Here, we demonstrate the pervasive augmentation of the miRNA-mediated translational repression of cellular mRNAs by NSP2. We show that NSP2 interacts with Argonaute 2, the core component of the miRNA-Induced Silencing Complex (miRISC) and enhances the translational repression mediated by natural miRNA binding sites in the 3 UTR of cellular mRNAs. Our data reveal an additional layer of the complex mechanism by which SARS-CoV-2 and likely other coronaviruses manipulate the host gene expression program through co-opting the host miRNA-mediated silencing machinery.

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Naeli, P., Zhang, X., Harris Snell, P., Chatterjee, S., Kamran, M., Ladak, R. J., Orr, N., Duchaine, T., Sonenberg, N., Jafarnejad, S. M.. 2023-01-03. SARS-CoV-2 protein NSP2 enhances microRNA-mediated translational repression. https://doi.org/10.1101/2023.01.01.522328

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