GSE193732
Cap-independent translation and a precisely localized RNA sequence enable SARS-CoV-2 to control host translation and escape anti-viral response
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 Overall design: RNA-seq of a time course of ActD-treated HEK293 cells over-expressing GFP or SARS-CoV-2 NSP1 , in order to calculate transcript half-lives