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

Thomas Kehrer et al. bioRxiv. .

Update in

  • Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis.
    Kehrer T, Cupic A, Ye C, Yildiz S, Bouhaddou M, Crossland NA, Barrall EA, Cohen P, Tseng A, Çağatay T, Rathnasinghe R, Flores D, Jangra S, Alam F, Mena I, Aslam S, Saqi A, Rutkowska M, Ummadi MR, Pisanelli G, Richardson RB, Veit EC, Fabius JM, Soucheray M, Polacco BJ, Ak B, Marin A, Evans MJ, Swaney DL, Gonzalez-Reiche AS, Sordillo EM, van Bakel H, Simon V, Zuliani-Alvarez L, Fontoura BMA, Rosenberg BR, Krogan NJ, Martinez-Sobrido L, García-Sastre A, Miorin L. Kehrer T, et al. Cell Host Microbe. 2023 Oct 11;31(10):1668-1684.e12. doi: 10.1016/j.chom.2023.08.003. Epub 2023 Sep 21. Cell Host Microbe. 2023. PMID: 37738983 Free PMC article.

Abstract

We and others have previously shown that the SARS-CoV-2 accessory protein ORF6 is a powerful antagonist of the interferon (IFN) signaling pathway by directly interacting with Nup98-Rae1 at the nuclear pore complex (NPC) and disrupting bidirectional nucleo-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 show that ORF6 plays a key role in the antagonism of IFN signaling and in viral pathogenesis by interfering with karyopherin(importin)-mediated nuclear import during SARS-CoV-2 infection both in vitro , and in the Syrian golden hamster model in vivo . In addition, we found that ORF6-Nup98 interaction also contributes to inhibition of cellular mRNA export during SARS-CoV-2 infection. As a result, 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 and demonstrated that it is able to disrupt ORF6 protein functions at the NPC and to impair SARS-CoV-2 innate immune evasion strategies. Importantly, the now more abundant Omicron BA.5 lacks this loss-of-function polymorphism in ORF6. 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 and its evolving variants.

One sentence summary: SARS-CoV-2 ORF6 subverts bidirectional nucleo-cytoplasmic trafficking to inhibit host gene expression and contribute to viral pathogenesis.

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