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Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis

ABSTRACT: We and others have previously shown that the SARS-CoV-2 accessory protein ORF6 is a powerful antagonist of the interferon signaling pathway by directly interacting with the Nup98-Rae1 complex at the nuclear pore, and disrupting bi-directional nuclear-cytoplasmic trafficking. In this study, we further assessed the role of ORF6 during infection using recombinant SARS-CoV-2 viruses carrying either a deletion or a well characterized M58R loss-of-function mutation in ORF6. We unambiguously show that ORF6 plays a key non-redundant role in the antagonism of IFN signaling by interfering with karyopherin-mediated nuclear import during SARS-CoV-2 infection both in vitro, and in the Syrian hamster model in vivo. In addition, we found that by contributing to the inhibition of cellular mRNA export, ORF6 expression significantly remodels the host cell proteome upon infection. Importantly, we also unravel a previously unrecognized function of ORF6 in the modulation of viral protein expression, which is independent of its function at the nuclear pore. Lastly, we characterized the ORF6 D61L mutation that recently emerged in Omicron BA.2 and BA.4 subvariants and demonstrated that it is able to disrupt ORF6 protein functions at the NPC and to impair SARS-CoV-2 innate immune evasion strategies. Altogether, our findings not only further highlight the key role of ORF6 in the antagonism of the antiviral innate immune response, but also emphasize the importance of studying the role of non-spike mutations to better understand the mechanisms governing differential pathogenicity and immune evasion strategies of SARS-CoV-2.

ORGANISM(S): Homo sapiens

PROVIDER: GSE215433 | GEO | 2023/08/11

REPOSITORIES: GEO

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SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling

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