Sarbecovirus ORF6 proteins hamper the induction of interferon signaling. Kimura et al
The presence of an ORF6 gene distinguishes sarbecoviruses such as SARS-CoV and SARS-CoV-2 from other betacoronaviruses. Here, we show that ORF6 inhibits the induction of innate immune signaling including upregulation of type I IFN upon viral infection, as well as type I and III IFN signaling. Intriguingly, ORF6 proteins from SARS-CoV-2 lineages are more efficient antagonists of innate immunity than their orthologs from SARS-CoV lineages. Mutational analyses identified residues E46 and Q56 as important determinants of the antagonistic activity of SARS-CoV-2 ORF6. Moreover, we show that the anti-innate immune activity of ORF6 depends on its C-terminal region and ORF6 inhibits the nuclear translocation of IRF3. Finally, we identify naturally occurring frameshift/nonsense mutations that result in an inactivating truncation of ORF6 in approximately 0.2% of SARS-CoV-2 isolates. Altogether, our findings suggest that ORF6 contributes to the poor IFN activation observed in COVID-19 patients.