Key result
Nsp1 represses translation and promotes mRNA degradation only after ribosome engagement with the mRNA, with specific N-terminal residues required for RNA degradation but not bulk translation shutoff.
Why the study?
It was unclear how SARS-CoV-2 Nsp1 translational repression and host RNA decay activities are connected and interact with normal translation processes.
The study reveals that SARS-CoV-2 Nsp1-mediated host mRNA degradation requires prior engagement of the ribosome with the mRNA.
Does not yet inform antiviral strategies; leaves open Nsp1 targeting as hypothesis-generating for future mechanistic and translational work.
Nsp1 is a SARS-CoV-2 host shutoff factor that both represses cellular translation and promotes host RNA decay. However, it is unclear how these two activities are connected and interact with normal translation processes. Here, we performed mutational analyses of Nsp1, and these revealed that both the N and C terminal domains of Nsp1 are important for translational repression. Furthermore, we demonstrate that specific residues in the N terminal domain are required for cellular RNA degradation but not bulk translation shutoff of host mRNAs, thereby separating RNA degradation from translation repression. We also present evidence that Nsp1 mediated RNA degradation requires engagement of the ribosome with mRNA. First, we observe that cytosolic lncRNAs, which are not translated, escape Nsp1 mediated degradation. Second, inhibition of translation elongation with emetine does not prevent Nsp1 mediated degradation, while blocking translation initiation before 48S ribosome loading reduces mRNA degradation. Taken together, we suggest that Nsp1 represses translation and promotes mRNA degradation only after ribosome engagement with the mRNA. This raises the possibility that Nsp1 may trigger RNA degradation through pathways that recognize stalled ribosomes.
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Shehata et al. (2023) studied SARS-CoV-2. Nsp1 mutational analysis was evaluated on Mechanisms of Nsp1 mediated mRNA degradation and translation repression. Nsp1 represses translation and promotes mRNA degradation only after ribosome engagement with the mRNA, with specific N-terminal residues required for RNA degradation but not bulk translation shutoff.
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