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

Thomas Kehrer, Anastasija Cupic, Chengjin Ye, Soner Yildiz, Mehdi Bouhaddou, Nicholas A. Crossland, Erika A. Barrall, Phillip Cohen, Anna Tseng, Tolga Çağatay, Raveen Rathnasinghe, Daniel Flores, Sonia Jangra, Fahmida Alam, Ignacio Mena, Sadaf Aslam, Anjali Saqi, Magdalena Rutkowska, Manisha R. Ummadi, Giuseppe PisanelliR. Blake Richardson, Ethan C. Veit, Jacqueline M. Fabius, Margaret Soucheray, Benjamin J. Polacco, Baran Ak, Arturo Marin, Matthew J. Evans, Danielle L. Swaney, Ana S. Gonzalez-Reiche, Emilia M. Sordillo, Harm van Bakel, Viviana Simon, Lorena Zuliani-Alvarez, Beatriz M.A. Fontoura, Brad R. Rosenberg, Nevan J. Krogan, Luis Martinez-Sobrido, Adolfo García-Sastre, Lisa Miorin

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.

Original languageEnglish
Pages (from-to)1668-1684.e12
JournalCell Host and Microbe
Issue number10
StatePublished - 11 Oct 2023


  • ORF6
  • Omicron variant
  • SARS-CoV-2
  • SARS-CoV-2 pathogenesis
  • interferon
  • mRNA export
  • nuclear import
  • nucleocytoplasmic trafficking
  • virus-host interaction


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