SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling
By Lisa Miorin, Thomas Kehrer, M. T. Sánchez-Aparicio, Ke Zhang, Phillip Cohen, Roosheel S. Patel, Anastasija Cupic, T. Makio, Menghan Mei, Elena Moreno and 17 more. 2020
501 citations recorded by the source corpus.
Significance To successfully establish infection, viral pathogens have to overcome the interferon (IFN)-mediated antiviral response. Previous studies revealed that the viral accessory protein Orf6 of SARS-CoV and SARS-CoV-2 is able to inhibit STAT1 nuclear translocation to block IFN signaling. In this study, we report that Orf6 localizes at the nuclear pore complex (NPC) where it binds directly to the Nup98-Rae1 complex to target the nuclear import pathway and mediate this inhibition. A better understanding of the strategies used by viruses to subvert host immune responses is critical for the design of novel antivirals and vaccines. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic that is a serious global health problem. Evasion of IFN-mediated antiviral signaling is a common defense strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to efficiently block STAT1 and STAT2 nuclear translocation in order to impair transcriptional induction of IFN-stimulated genes (ISGs). Our results demonstrate that the viral accessory protein Orf6 exerts this anti-IFN activity. We found that SARS-CoV-2 Orf6 localizes at the nuclear pore complex (NPC) and directly interacts with Nup98-Rae1 via its C-terminal domain to impair docking of cargo-receptor (karyopherin/importin) complex and disrupt nuclear import. In addition, we show that a methionine-to-arginine substitution at residue 58 impairs Orf6 binding to the Nup98-Rae1 complex and abolishes its IFN antagonistic function. All together our data unravel a mechanism of viral antagonism in which a virus hijacks the Nup98-Rae1 complex to overcome the antiviral action of IFN.
Subfields: Animal Science and Zoology, Immunology, Infectious Diseases
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In Immunology
Citations in the corpus
- Sarbecovirus ORF6 proteins hamper induction of interferon signaling (2021, unknown): “Consistent with previous studies characterizing ORF6 of SARS-CoV-2 (Miorin et al., 2020) or SARS-CoV (Kopecky-Bromberg et al.”
- Characterization of SARS-CoV-2 proteins reveals Orf6 pathogenicity, subcellular localization, host interactions and attenuation by Selinexor (2021, unknown): “SARS-CoV-2, and its predecessor SARS-CoV, target the nuclear import of STAT1 and STAT2 to impede the induction of IFN-stimulated genes [28].”
- Host cell-intrinsic innate immune recognition of SARS-CoV-2 (2021, unknown): “Nsp1, Nsp6, Nsp13, Nsp14, ORF3a, ORF7a, and ORF7b all have been reported to prevent or reduce phosphorylation of STAT1 and 2 [71 ,78].”
- Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1–Nup98 Complex to Compete With mRNA Nuclear Export (2022, methodology): “identified the interactions between SARS-CoV-2 Orf6 and the Rae1–Nup98 complex for the first time in 2020, and some other convincing evidence was published thereafter (Gordon et al., 2020; Lei et al., 2020; Miorin et al., 2020; Addetia et al., 2021).”
- Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant (2021, background): “Orf6 is known to antagonise the innate response through inhibition of transcription factor STAT1 and IRF3 nuclear entry 13,24 .”
- SARS-CoV-2 ORF6 Disrupts Bidirectional Nucleocytoplasmic Transport through Interactions with Rae1 and Nup98 (2021, background): “Both SARS-CoV and SARS-CoV-2 have been demonstrated to block nuclear import of the transcription factor, STAT1, during infection in cell culture (3, 14).”