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

Parisa Naeli, Xu Zhang, Patric Harris Snell, Susanta Chatterjee, Muhammad Kamran, Reese Jalal Ladak, Nick Orr, Thomas Duchaine, Nahum Sonenberg, Seyed Mehdi Jafarnejad*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Viruses use microRNAs (miRNAs) to impair the host antiviral response and facilitate viral infection by expressing their own miRNAs or co-opting cellular miRNAs. miRNAs inhibit translation initiation of their target mRNAs by recruiting the GIGYF2–4EHP (or EIF4E2) translation repressor complex to the mRNA 5′-cap structure. 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 Ifnb1 mRNA that encodes the cytokine interferon β, and thereby impairs the host antiviral response. However, it is not known whether NSP2 also affects miRNA-mediated silencing. Here, we demonstrate the pervasive augmentation of miRNA-mediated translational repression of cellular mRNAs by NSP2. We show that NSP2 interacts with argonaute 2 (AGO2), the core component of the miRNA-induced silencing complex (miRISC), via GIGYF2 and enhances the translational repression mediated by natural miRNA-binding sites in the 3′ untranslated region 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 by co-opting the host miRNA-mediated silencing machinery.

Original languageEnglish
Article numberjcs261286
Number of pages10
JournalJournal of Cell Science
Volume136
Issue number19
Early online date21 Sept 2023
DOIs
Publication statusPublished - Oct 2023

Keywords

  • 4EHP
  • GIGYF2
  • NSP2
  • SARS-CoV-2
  • mRNA translation
  • microRNA

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