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

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

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284 Scopus citations


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.

Original languageEnglish
Pages (from-to)28344-28354
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number45
StatePublished - 10 Nov 2020


  • SARS-CoV-2 | interferon signaling antagonism | STATs | ORF6 | Nup98


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