Key result
SARS-CoV-2 NSP1 enhances expression of viral mRNAs containing the leader sequence, requiring specific residues in stem-loop 1 (C15, C19, C20) and NSP1 (R124) for viral evasion.
Why the study?
SARS-CoV-2 NSP1 inhibits host translation by blocking the ribosomal mRNA entry tunnel, but the mechanisms by which viral mRNAs overcome this blockade and reconcile conflicting literature remained to be determined.
Identifies specific residues in SARS-CoV-2 SL1 and NSP1 required for viral evasion of host translation inhibition, presenting potential drug targets.
NSP1 selectively blocks host translation; leaves open whether targeting viral mRNA evasion alters COVID-19 outcomes.
SARS-CoV-2, responsible for the ongoing global pandemic, must overcome a conundrum faced by all viruses. To achieve its own replication and spread, it simultaneously depends on and subverts cellular mechanisms. At the early stage of infection, SARS-CoV-2 expresses the viral nonstructural protein 1 (NSP1), which inhibits host translation by blocking the mRNA entry tunnel on the ribosome; this interferes with the binding of cellular mRNAs to the ribosome. Viral mRNAs, on the other hand, overcome this blockade. We show that NSP1 enhances expression of mRNAs containing the SARS-CoV-2 leader. The first stem-loop (SL1) in viral leader is both necessary and sufficient for this enhancement mechanism. Our analysis pinpoints specific residues within SL1 (three cytosine residues at the positions 15, 19 and 20) and another within NSP1 (R124) which are required for viral evasion, and thus might present promising drug targets. Additionally, we carried out analysis of a functional interactome of NSP1 using BioID and identified components of anti-viral defense pathways. Our analysis therefore suggests a mechanism by which NSP1 inhibits the expression of host genes while enhancing that of viral RNA. This analysis helps reconcile conflicting reports in the literature regarding the mechanisms by which the virus avoids NSP1 silencing.
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Bujanic et al. (2021) studied SARS-CoV-2. NSP1 and SARS-CoV-2 leader sequence was evaluated on Viral mRNA expression and evasion of NSP1 repression. SARS-CoV-2 NSP1 enhances expression of viral mRNAs containing the leader sequence, requiring specific residues in stem-loop 1 (C15, C19, C20) and NSP1 (R124) for viral evasion.