Key result
SARS-CoV-2 Nsp1 binds to the human 40S ribosomal subunit and inserts its C-terminal domain into the mRNA channel, potently inhibiting host translation while allowing viral mRNA translation.
SARS-CoV-2 Nsp1 inhibits host translation by binding to the 40S ribosomal mRNA channel, while viral mRNA with its full-length 5' UTR is efficiently translated, providing a mechanism for viral evasion and replication.
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Nsp1-40S binding may guide antiviral design; leaves open clinical translation in COVID-19.
The non-structural protein 1 (Nsp1), also referred to as the host shutoff factor, is the first viral protein that is synthesized in SARS-CoV-2 infected human cells to suppress host innate immune functions 1,2 . By combining cryo-electron microscopy and biochemical experiments, we show that SARS-CoV-2 Nsp1 binds to the human 40S subunit in ribosomal complexes including the 43S pre-initiation complex. The protein inserts its C-terminal domain at the entrance to the mRNA channel where it interferes with mRNA binding. We observe potent translation inhibition in the presence of Nsp1 in lysates from human cells. Based on the high-resolution structure of the 40S-Nsp1 complex, we identify residues of Nsp1 crucial for mediating translation inhibition. We further show that the full-length 5’ untranslated region of the genomic viral mRNA stimulates translation in vitro , suggesting that SARS-CoV-2 combines inhibition of translation by Nsp1 with efficient translation of the viral mRNA to achieve expression of viral genes 3 .
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Schubert et al. (2020) studied SARS-CoV-2 infection. SARS-CoV-2 Nsp1 vs. Control (no Nsp1) or mutant Nsp1 was evaluated on In vitro translation inhibition. SARS-CoV-2 Nsp1 binds to the human 40S ribosomal subunit and inserts its C-terminal domain into the mRNA channel, potently inhibiting host translation while allowing viral mRNA translation.
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