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Sarbecovirus ORF6 proteins antagonize interferon signaling
Topics in Antiviral Medicine ; 29(1):29, 2021.
Article in English | EMBASE | ID: covidwho-1250364
ABSTRACT

Background:

SARS-CoV and SARS-CoV-2 are closely related, both belong to the genus Betacoronavirus, subgenus Sarbecovirus. The ORF6 gene is commonly encoded in all Sarbecoviruses, including SARS-CoV and SARS-CoV-2, while no orthologs are found in the other Betacoronaviruses. A comprehensive proteome analysis by Gordon et al. has recently suggested that SARS-CoV-2 ORF6 interacts with two cellular proteins, RAE1 and NUP98, via its C-terminal region, but the biological function of ORF6 remains unknown.

Methods:

For the cell culture experiments, we generated a series of Sarbecovirus ORF6 expression plasmids. We monitored human IFNB1 promoter activity in the presence of ORF6 by a luciferase reporter assay. To determine the residue(s) that are responsible for the anti-interferon (IFN) activity of ORF6, we aligned and compared the ORF6 amino acid sequences and prepared a series of ORF6 mutants. To verify whether ORF6 interacts with RAE1 and NUP98 proteins, we performed co-immunoprecipitation assay.

Results:

The cell culture experiments showed that ORF6 inhibits the induction of type I IFN upon viral infection. Intriguingly, the anti-IFN activity of ORF6 proteins of SARS-CoV-2 lineages was more potent than that of SARS-CoV lineages. Mutational analyses identified the two residues in the C-terminal region of ORF6 that determines the difference on the anti-IFN activity between SARS-CoV-2 ORF6 and SARS-CoV ORF6. Moreover, the co-immunoprecipitation assay revealed that ORF6 binds to RAE1 and NUP98 via its C-terminus, thereby inhibiting the expression of IFNB1 mRNA. Finally, in approximately 0.2% of the SARS-CoV-2 isolates during current pandemic, we identified naturally occurring variants that encode the truncated ORF6 gene by frameshift mutation and potentially result in the incompetence of exhibiting anti-IFN effect.

Conclusion:

Our findings suggest that the poor IFN activation observed in COVID-19 patients can at least in part be ascribed to ORF6. Furthermore, we provide evidence suggesting that the emergence of the SARS-CoV-2 variants that lost a functional ORF6 gene may contribute to the attenuation of viral pathogenicity.
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Collection: Databases of international organizations Database: EMBASE Language: English Journal: Topics in Antiviral Medicine Year: 2021 Document Type: Article

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Collection: Databases of international organizations Database: EMBASE Language: English Journal: Topics in Antiviral Medicine Year: 2021 Document Type: Article