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The key features of SARS-CoV-2 leader and NSP1 required for viral escape of NSP1-mediated repression

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Item Type:Article
Title:The key features of SARS-CoV-2 leader and NSP1 required for viral escape of NSP1-mediated repression
Creators Name:Bujanic, L. and Shevchuk, O. and von Kügelgen, N. and Kalinina, A. and Ludwik, K. and Koppstein, D. and Zerna, N. and Sickmann, A. and Chekulaeva, M.
Abstract: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. We target SL1 with the anti-sense oligo (ASO) to efficiently and specifically downregulate SARS-CoV-2 mRNA. 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.
Keywords:COVID-19, Messenger RNA, Ribosomes, SARS-CoV-2, Viral Nonstructural Proteins
Publisher:RNA Society
Page Range:766-779
Date:May 2022
Official Publication:https://doi.org/10.1261/rna.079086.121
PubMed:View item in PubMed
Related to:
https://edoc.mdc-berlin.de/20934/Preprint version

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