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The SARS-CoV-2 nucleocapsid protein interferes with the full enzymatic activation of UPF1 and its interaction with UPF2.
Nucleic Acids Res, 53(2).
The nonsense-mediated mRNA decay (NMD) pathway triggers the degradation ofdefective mRNAs and governs the expression of mRNAs with specificcharacteristics. Current understanding indicates that NMD is often significantlysuppressed during viral infections to protect the viral genome. In numerousviruses, this inhibition is achieved through direct or indirect interference withthe RNA helicase UPF1, thereby promoting viral replication and enhancingpathogenesis. In this study, we employed biochemical, biophysical assays andcellular investigations to explore the interplay between UPF1 and thenucleocapsid (Np) protein of SARS-CoV-2. We evaluated their direct interactionand its impact on inhibiting cellular NMD. Furthermore, we characterized how thisinteraction affects UPF1's enzymatic function. Our findings demonstrate that Npinhibits the unwinding activity of UPF1 by physically obstructing its access tostructured nucleic acid substrates. Additionally, we showed that Np bindsdirectly to UPF2, disrupting the formation of the UPF1/UPF2 complex essential forNMD progression. Intriguingly, our research also uncovered a surprising pro-viralrole of UPF1 and an antiviral function of UPF2. These results unveil a novel,multi-faceted mechanism by which SARS-CoV-2 evades the host's defenses andmanipulates cellular components. This underscores the potential therapeuticstrategy of targeting Np-UPF1/UPF2 interactions to treat COVID-19.
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