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

  • Author(s): Miorin, Lisa;
  • Kehrer, Thomas;
  • Sanchez-Aparicio, Maria Teresa;
  • Zhang, Ke;
  • Cohen, Phillip;
  • Patel, Roosheel S;
  • Cupic, Anastasija;
  • Makio, Tadashi;
  • Mei, Menghan;
  • Moreno, Elena;
  • Danziger, Oded;
  • White, Kris M;
  • Rathnasinghe, Raveen;
  • Uccellini, Melissa;
  • Gao, Shengyan;
  • Aydillo, Teresa;
  • Mena, Ignacio;
  • Yin, Xin;
  • Martin-Sancho, Laura;
  • Krogan, Nevan J;
  • Chanda, Sumit K;
  • Schotsaert, Michael;
  • Wozniak, Richard W;
  • Ren, Yi;
  • Rosenberg, Brad R;
  • Fontoura, Beatriz MA;
  • García-Sastre, Adolfo
  • et al.
Abstract

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.

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