TY - JOUR
T1 - SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling
AU - Miorin, Lisa
AU - Kehrer, Thomas
AU - Sanchez-Aparicio, Maria Teresa
AU - Zhang, Ke
AU - Cohen, Phillip
AU - Patel, Roosheel S.
AU - Cupic, Anastasija
AU - Makio, Tadashi
AU - Mei, Menghan
AU - Moreno, Elena
AU - Danziger, Oded
AU - White, Kris M.
AU - Rathnasinghe, Raveen
AU - Uccellini, Melissa
AU - Gao, Shengyan
AU - Aydillo, Teresa
AU - Mena, Ignacio
AU - Yin, Xin
AU - Martin-Sancho, Laura
AU - Krogan, Nevan J.
AU - Chanda, Sumit K.
AU - Schotsaert, Michael
AU - Wozniak, Richard W.
AU - Ren, Yi
AU - Rosenberg, Brad R.
AU - Fontoura, Beatriz M.A.
AU - García-Sastre, Adolfo
N1 - Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/11/10
Y1 - 2020/11/10
N2 - 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.
AB - 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.
KW - SARS-CoV-2 | interferon signaling antagonism | STATs | ORF6 | Nup98
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U2 - 10.1073/pnas.2016650117
DO - 10.1073/pnas.2016650117
M3 - Article
C2 - 33097660
AN - SCOPUS:85096080108
SN - 0027-8424
VL - 117
SP - 28344
EP - 28354
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
ER -