SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling.
Active Transport, Cell Nucleus
Animals
Binding Sites
COVID-19
/ metabolism
Chlorocebus aethiops
HEK293 Cells
Humans
Interferons
/ metabolism
Nuclear Matrix-Associated Proteins
/ chemistry
Nuclear Pore
/ metabolism
Nuclear Pore Complex Proteins
/ metabolism
Nucleocytoplasmic Transport Proteins
/ chemistry
Protein Binding
STAT1 Transcription Factor
/ metabolism
STAT2 Transcription Factor
/ metabolism
Signal Transduction
Vero Cells
Viral Proteins
/ metabolism
Nup98
ORF6
SARS-CoV-2
STATs
interferon signaling antagonism
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
10 11 2020
10 11 2020
Historique:
pubmed:
25
10
2020
medline:
15
12
2020
entrez:
24
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33097660
pii: 2016650117
doi: 10.1073/pnas.2016650117
pmc: PMC7668094
doi:
Substances chimiques
Nuclear Matrix-Associated Proteins
0
Nuclear Pore Complex Proteins
0
Nucleocytoplasmic Transport Proteins
0
Nup98 protein, human
0
ORF6 protein, SARS-CoV-2
0
RAE1 protein, human
0
STAT1 Transcription Factor
0
STAT1 protein, human
0
STAT2 Transcription Factor
0
STAT2 protein, human
0
Viral Proteins
0
Interferons
9008-11-1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
28344-28354Subventions
Organisme : NIH HHS
ID : 5R35GM133743
Pays : United States
Organisme : NIAID NIH HHS
ID : HHSN272201400008C
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI135990
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI154635
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM133743
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI118610
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI135972
Pays : United States
Informations de copyright
Copyright © 2020 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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