PT  - JOURNAL ARTICLE
AU  - Boris Slobodin
AU  - Urmila Sehrawat
AU  - Anastasia Lev
AU  - Ariel Ogran
AU  - Davide Fraticelli
AU  - Daniel Hayat
AU  - Binyamin Zuckerman
AU  - Igor Ulitsky
AU  - Amir Ben-Shmuel
AU  - Elad Bar-David
AU  - Haim Levy
AU  - Rivka Dikstein
TI  - Cap-independent translation and a precisely localized RNA sequence enable SARS-CoV-2 to control host translation and escape anti-viral response
AID  - 10.1101/2021.08.18.456855
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.08.18.456855
4099  - http://biorxiv.org/content/early/2021/08/18/2021.08.18.456855.short
4100  - http://biorxiv.org/content/early/2021/08/18/2021.08.18.456855.full
AB  - Translation of SARS-CoV-2-encoded mRNAs by the host ribosomes is essential for its propagation. Following infection, the early expressed viral protein NSP1 binds the ribosome, represseses translation and induces mRNA degradation, while the host elicits anti-viral response. The mechanisms enabling viral mRNAs to escape this multifaceted repression remain obscure. Here we show that expression of NSP1 leads to destabilization of multi-exon cellular mRNAs, while intron-less transcripts, such as viral mRNAs and anti-viral interferon genes, remain relatively stable. We identified a conserved and precisely located cap-proximal RNA element devoid of guanosines that confers resistance to NSP1-meidated translation inhibition. Importantly, the primary sequence rather than the secondary structure is critical for protection. We further show that the genomic 5’UTR of SARS-CoV-2 exhibits an IRES-like activity and promotes expression of NSP1 in an eIF4E-independent and Torin-1 resistant manner. Upon expression, NSP1 enhances cap-independent translation. However, the sub-genomic 5’UTRs are highly sensitive to eIF4E availability, rendering viral propagation partially sensitive to Torin-1. The combined NSP1-mediated degradation of spliced mRNAs and translation inhibition of single-exon genes, along with the unique features present in the viral 5’UTRs, ensure robust expression of viral mRNAs. These features can be exploited as potential therapeutic targets.Competing Interest StatementThe authors have declared no competing interest.