Sarbecovirus ORF6 proteins hamper induction of interferon signaling

Cell Reports

Kristina Hopfensperger¹  So Nakagawa²  Keiya Uriu³  Izumi Kimura³  Yoriyuki Konno³  Daniel Sauter⁴  Kei Sato⁴ 

[1] Graduate School of Medicine, The University of Tokyo, Tokyo 1130033, Japan;Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen 72076, Germany;Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan;Institute of Molecular Virology, Ulm University Medical Center, Ulm 89081, Germany;

关键词: SARS-CoV-2;    COVID-19;    ORF6;    type I interferon;    type III interferon;    interferon-stimulated gene;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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).

【 授权许可】

Unknown