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SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling
- Source :
- Proceedings of the National Academy of Sciences of the United States of America, vol 117, iss 45, Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences of the United States of America
- Publication Year :
- 2020
- Publisher :
- eScholarship, University of California, 2020.
-
Abstract
- Significance To successfully establish infection, viral pathogens have to overcome the interferon (IFN)-mediated antiviral response. Previous studies revealed that the viral accessory protein Orf6 of SARS-CoV and SARS-CoV-2 is able to inhibit STAT1 nuclear translocation to block IFN signaling. In this study, we report that Orf6 localizes at the nuclear pore complex (NPC) where it binds directly to the Nup98-Rae1 complex to target the nuclear import pathway and mediate this inhibition. A better understanding of the strategies used by viruses to subvert host immune responses is critical for the design of novel antivirals and vaccines.<br />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.
- Subjects :
- 0301 basic medicine
Nucleocytoplasmic Transport Proteins
viruses
0302 clinical medicine
Nuclear Matrix-Associated Proteins
Interferon
Chlorocebus aethiops
2.1 Biological and endogenous factors
STAT1
Aetiology
Nuclear pore
STAT2
Lung
Karyopherin
chemistry.chemical_classification
Multidisciplinary
Biological Sciences
ORF6
Active Transport
3. Good health
Cell biology
Nup98
Infectious Diseases
STAT1 Transcription Factor
5.1 Pharmaceuticals
030220 oncology & carcinogenesis
Pneumonia & Influenza
Development of treatments and therapeutic interventions
Infection
Biotechnology
medicine.drug
Signal Transduction
Protein Binding
Active Transport, Cell Nucleus
Importin
Biology
Microbiology
Virus
interferon signaling antagonism
Vaccine Related
STATs
03 medical and health sciences
Viral Proteins
Biodefense
medicine
Animals
Humans
Vero Cells
Cell Nucleus
Binding Sites
SARS-CoV-2
Prevention
COVID-19
STAT2 Transcription Factor
Pneumonia
Nuclear Pore Complex Proteins
Emerging Infectious Diseases
030104 developmental biology
HEK293 Cells
chemistry
biology.protein
Nuclear Pore
Immunization
Interferons
Nuclear transport
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America, vol 117, iss 45, Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....555020bad50a2c2b24a24935300a51f0