Clinically observed deletions in SARS‐CoV‐2 Nsp1 affect its stability and ability to inhibit translation

Nonstructural protein 1 (Nsp1) of SARS‐CoV‐2 inhibits host cell translation through an interaction between its C‐terminal domain and the 40S ribosome. The N‐terminal domain (NTD) of Nsp1 is a target of recurring deletions, some of which are associated with altered COVID‐19 disease progression. Here, we characterize the efficiency of translational inhibition by clinically observed Nsp1 deletion variants. We show that a frequent deletion of residues 79–89 severely reduces the ability of Nsp1 to inhibit translation while not abrogating Nsp1 binding to the 40S. Notably, while the SARS‐CoV‐2 5′ untranslated region enhances translation of mRNA, it does not protect from Nsp1‐mediated inhibition. Finally, thermal stability measurements and structure predictions reveal a correlation between stability of the NTD and the efficiency of translation inhibition.