Sarbecovirus ORF6 proteins hamper induction of interferon signaling

Izumi Kimura,Yoriyuki Konno,Keiya Uriu,Kristina Hopfensperger,Daniel Sauter,So Nakagawa,Kei Sato

doi:10.1016/j.celrep.2021.108916

Abstract

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).

Highlights

An unusual outbreak of infectious pneumonia in Wuhan, Hubei Province, China, was first reported in December 2019
We show that an ORF6 gene is commonly encoded in all sarbecoviruses, including severe acute respiratory syndrome (SARS)-CoV and SARSCoV-2, whereas no orthologs are found in other betacoronaviruses, such as Middle East respiratory syndrome (MERS)-CoV, OC43, and murine hepatitis virus (MHV)
ORF6 is conserved in the subgenus Sarbecovirus but absent from other betacoronaviruses We first assessed the phylogenetic relationship of betacoronaviruses, including SARS-CoV, SARS-CoV-2, MERS-CoV, OC43, and HKU1

Summary

Introduction

An unusual outbreak of infectious pneumonia in Wuhan, Hubei Province, China, was first reported in December 2019. A novel coronavirus (CoV) was identified as the causative agent of this infectious disease, CoV disease 2019 (COVID19) (Zhou et al, 2020b). Because this virus is phylogenetically related to severe acute respiratory syndrome (SARS)-CoV, it was called SARS-CoV-2. SARS-CoV-2-related viruses have been identified in intermediate horseshoe bats (Rhinolophus affinis) (Zhou et al, 2020b) and a Malayan horseshoe bat (Rhinolophus malayanus) (Zhou et al, 2020a) as well as Malayan pangolins (Manis javanica) (Lam et al, 2020; Xiao et al, 2020). This suggests that zoonotic viral transmission from horseshoe bats to humans led to emergence of human pathogenic sarbecoviruses, including SARS-CoV and SARS-CoV-2

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