PT  - JOURNAL ARTICLE
AU  - Lucija Bujanic
AU  - Olga Shevchuk
AU  - Nicolai von Kügelgen
AU  - Katarzyna Ludwik
AU  - David Koppstein
AU  - Nadja Zerna
AU  - Albert Sickmann
AU  - Marina Chekulaeva
TI  - The key features of SARS-CoV-2 leader and NSP1 required for viral escape of NSP1-mediated repression
AID  - 10.1101/2021.09.13.460054
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.09.13.460054
4099  - http://biorxiv.org/content/early/2021/09/13/2021.09.13.460054.short
4100  - http://biorxiv.org/content/early/2021/09/13/2021.09.13.460054.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.