Mutational screening reveals a cluster of residues within the SARS-CoV-2 nsp1 N-terminus that confers RNA-targeting selectivity
The SARS-CoV-2 nsp1 protein is a virulence factor that broadly inhibits cellular gene expression. Although cellular mRNAs are translationally inhibited by nsp1 and subsequently degraded, viral transcripts possess a 5' leader sequence (CoV2L) that enables them to escape nsp1-mediated repression. Both transcript targeting selectivity and mRNA decay require coordination by the nsp1 N-terminal domain…
Research into the SARS-CoV-2 nsp1 protein has uncovered a crucial cluster of residues within its N-terminus that determines the protein's selective targeting of RNA. The nsp1 protein acts as a virulence factor, inhibiting cellular gene expression by repressing host mRNAs and allowing viral mRNA to escape degradation. However, the precise mechanism by which the nsp1 N-terminal domain (NTD) coordinates selectivity and mRNA decay remains unknown.
To tackle this mystery, researchers created an alanine-scanning library of mutations across all residues in the nsp1 NTD. This library was screened for its ability to repress mRNAs bearing either host or CoV2L-derived 5' untranslated regions. The screening revealed two main clusters of residues within the NTD that are essential for target selectivity.
These residues primarily consist of adjacent surface-exposed beta-sheets on the NTD. When these beta-sheets are removed, mRNAs containing the CoV2L-derived 5' untranslated region become susceptible to repression by nsp1 and are no longer subject to nsp1-induced mRNA decay. This study provides detailed residue-level insights into the NTD's role in distinguishing between different types of mRNA targets and establishes a link between nsp1's target selectivity and mRNA decay.
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