SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling.
Lisa Miorin,Thomas Kehrer,Maria Teresa Sánchez-Aparicio,Ke Zhang,Phillip Cohen,Roosheel S. Patel,Anastasija Cupic,Tadashi Makio,Menghan Mei,Elena Moreno,Oded Danziger,Kris M. White,Raveen Rathnasinghe,Melissa B. Uccellini,Shengyan Gao,Teresa Aydillo,Ignacio Mena,Xin Yin,Laura Martin-Sancho,Nevan J. Krogan,Nevan J. Krogan,Nevan J. Krogan,Sumit K. Chanda,Michael Schotsaert,Richard W. Wozniak,Yi Ren,Brad R. Rosenberg,Beatriz M. A. Fontoura,Adolfo García-Sastre +28 more
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TLDR
SARS-CoV-2 is able to efficiently block STAT1 and STAT2 nuclear translocation in order to impair transcriptional induction of IFN-stimulated genes (ISGs).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.read more
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