The molecular strategies employed by SARS-CoV-2 for inhibiting host mRNAs and promoting viral transcripts

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, represses translation, and induces mRNA degradation, while the host elicits an anti-viral response. The mechanisms enabling viral mRNAs to escape this multifaceted repression remain obscure. We show that the expression of NSP1 leads to a massive destabilisation of multi-exon cellular mRNAs. In contrast, intron-less transcripts, a group of genes that contains both viral mRNAs and anti-viral interferon genes, remain less affected. Further, we identified a conserved and precisely located cap-proximal RNA element devoid of guanosines that confers resistance to NSP1-mediated translation inhibition. Notably, the primary sequence rather than the secondary structure is critical for the observed protection and sufficient to enhance the expression of random transcripts in NSP1-expressing cells. We further show that the genomic 5’UTR of SARS-CoV-2 drives cap-independent translation and promotes expression of NSP1 in an eIF4E-independent and Torin1-resistant manner. Interestingly, when expressed, NSP1 further enhances cap-independent translation. In contrast, the sub-genomic viral 5’UTRs are highly sensitive to eIF4E availability, rendering viral propagation partially vulnerable to inhibitors of cap-dependent translation. Summarily, we conclude that 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 SARS-CoV-2 transcripts.