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

• Published in: Cell host & microbe Vol. 31; no. 10; pp. 1668 - 1684.e12
• Main Authors: Kehrer, Thomas, Cupic, Anastasija, Ye, Chengjin, Yildiz, Soner, Bouhaddou, Mehdi, Crossland, Nicholas A., Barrall, Erika A., Cohen, Phillip, Tseng, Anna, Çağatay, Tolga, Rathnasinghe, Raveen, Flores, Daniel, Jangra, Sonia, Alam, Fahmida, Mena, Ignacio, Aslam, Sadaf, Saqi, Anjali, Rutkowska, Magdalena, Ummadi, Manisha R., Pisanelli, Giuseppe, Richardson, R. Blake, Veit, Ethan C., Fabius, Jacqueline M., Soucheray, Margaret, Polacco, Benjamin J., Ak, Baran, Marin, Arturo, Evans, Matthew J., Swaney, Danielle L., Gonzalez-Reiche, Ana S., Sordillo, Emilia M., van Bakel, Harm, Simon, Viviana, Zuliani-Alvarez, Lorena, Fontoura, Beatriz M.A., Rosenberg, Brad R., Krogan, Nevan J., Martinez-Sobrido, Luis, García-Sastre, Adolfo, Miorin, Lisa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.10.2023
• Subjects: COVID-19 - virology; Humans; Immunity, Innate; interferon; Interferons - genetics; Interferons - metabolism; mRNA export; nuclear import; nucleocytoplasmic trafficking; Omicron variant; ORF6; SARS-CoV-2; SARS-CoV-2 - genetics; SARS-CoV-2 pathogenesis; Viral Proteins - genetics; Viral Proteins - metabolism; virus-host interaction; virus-host interaction; SARS-CoV-2 pathogenesis; mRNA export; Omicron variant; SARS-CoV-2; nucleocytoplasmic trafficking; ORF6; interferon; nuclear import
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2023.08.003

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. [Display omitted] •SARS-CoV-2 ORF6 antagonizes IFN-induced signaling during infection•ORF6 binds Nup98-Rae1 and selectively inhibits nucleocytoplasmic trafficking•ORF6 expression contributes to SARS-CoV-2 pathogenesis•The D61L polymorphism disrupts ORF6 protein functions at the NPC Kehrer, Cupic et al. dissect the role of ORF6 in the host response to SARS-CoV-2 infection. ORF6 is an innate immune antagonist that binds to Nup98-Rae1 and suppresses host gene expression by selectively inhibiting nucleocytoplasmic trafficking. ORF6 loss-of-function mutations result in SARS-CoV-2 attenuation both in vitro and in vivo.