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 - Funding Information:
ACKNOWLEDGMENTS. We thank all the members of the A.G.-S. laboratory for helpful feedback. We thank Randy Albrecht for support with the BSL3 facility and procedures at the Icahn School of Medicine at Mount Sinai (ISMMS), and Richard Cadagan for technical assistance. We thank Dr. X. Sun (Cross Cancer Institute, University of Alberta) for assistance with the STED microscopy. Confocal microscope images were taken at the Microscopy Shared Resource Facility at the ISMMS. This research was partly funded by Center for Research for Influenza Pathogenesis, a National Institute of Allergy and Infectious Diseases (NIAID) supported Center of Excellence for Influenza Research and Surveillance (contract HHSN272201400008C); by the Defense Advanced Research Projects Agency (DARPA) grant HR0011-19-20020; by the generous support of the JPB Foundation, the Open Philanthropy Project [research grant 2020-215611 (5384)]; by anonymous donors to A.G.-S.; by the Department of Microbiology, ISMMS; by NIH 1 R01 AI154635 to B.M.A.F.; by funding from the Canadian Institutes of Health Research (FRN: 156030) to R.W.W.; by the National Institute of General Medical Sciences (NIGMS) grant 5R35GM133743 to Y.R.; by the NIAID grants U19 AI118610 and U19 AI135972 to S.K.C.; and by a Mary Kay Foundation International Postdoctoral Scholar Fellowship to S.G.
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
UR - http://www.scopus.com/inward/record.url?scp=85096080108&partnerID=8YFLogxK
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 -