Sarbecovirus ORF6 proteins hamper induction of interferon signaling
By I. Kimura, Y. Konno, K. Uriu, Kristina Hopfensperger, D. Sauter, S. Nakagawa, Kei Sato. 2021
76 citations recorded by the source corpus.
The presence of an ORF6 gene distinguishes sarbecoviruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 from other betacoronaviruses. Here we show that ORF6 inhibits induction of innate immune signaling, including upregulation of type I interferon (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 that ORF6 inhibits 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. Our findings suggest that ORF6 contributes to the poor IFN activation observed in individuals with coronavirus disease 2019 (COVID-19).
Subfields: Animal Science and Zoology, Infectious Diseases
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- Tinghan Li
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Citations in the corpus
- Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1–Nup98 Complex to Compete With mRNA Nuclear Export (2022, background): “Coronaviruses from subgenus Sarbecovirus encode the ORF6 gene uniquely, and no orthologues have been found in other members from the genus Betacoronaviruses (Kimura et al., 2021).”