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Proceedings of the National Academy of Sciences of the United States of America
11 10, 2020;117 (45): 28344-28354.

SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling.

Lisa Miorin, Thomas Kehrer, Maria Teresa Sanchez-Aparicio, Ke Zhang, Phillip Cohen, Roosheel S Patel, Anastasija Cupic, Tadashi Makio, Menghan Mei, Elena Moreno, Oded Danziger, Kris M White, Raveen Rathnasinghe, Melissa Uccellini, Shengyan Gao, Teresa Aydillo, Ignacio Mena, Xin Yin, Laura Martin-Sancho, Nevan J Krogan, Sumit K Chanda, Michael Schotsaert, Richard W Wozniak, Yi Ren, Brad R Rosenberg, Beatriz M A Fontoura, Adolfo García-Sastre
Author Information
  1. Lisa Miorin: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; lisa.miorin@mssm.edu adolfo.garcia-sastre@mssm.edu. ORCID
  2. Thomas Kehrer: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  3. Maria Teresa Sanchez-Aparicio: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029. ORCID
  4. Ke Zhang: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390. ORCID
  5. Phillip Cohen: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029. ORCID
  6. Roosheel S Patel: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  7. Anastasija Cupic: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029. ORCID
  8. Tadashi Makio: Department of Cell Biology, University of Alberta, Edmonton, AB T6G 2H7, Canada.
  9. Menghan Mei: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232. ORCID
  10. Elena Moreno: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  11. Oded Danziger: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029. ORCID
  12. Kris M White: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  13. Raveen Rathnasinghe: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  14. Melissa Uccellini: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  15. Shengyan Gao: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390. ORCID
  16. Teresa Aydillo: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029. ORCID
  17. Ignacio Mena: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029. ORCID
  18. Xin Yin: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037. ORCID
  19. Laura Martin-Sancho: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
  20. Nevan J Krogan: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  21. Sumit K Chanda: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
  22. Michael Schotsaert: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  23. Richard W Wozniak: Department of Cell Biology, University of Alberta, Edmonton, AB T6G 2H7, Canada. ORCID
  24. Yi Ren: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232. ORCID
  25. Brad R Rosenberg: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029. ORCID
  26. Beatriz M A Fontoura: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390. ORCID
  27. Adolfo García-Sastre: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; lisa.miorin@mssm.edu adolfo.garcia-sastre@mssm.edu. ORCID
PMID: 33097660 DOI: 10.1073/pnas.2016650117

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.

Keywords

Nup98 ORF6 SARS-CoV-2 STATs interferon signaling antagonism

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Grants

  1. 5R35GM133743/NIH HHS
  2. HHSN272201400008C/NIAID NIH HHS
  3. U19 AI135990/NIAID NIH HHS
  4. R01 AI154635/NIAID NIH HHS
  5. R35 GM133743/NIGMS NIH HHS
  6. U19 AI118610/NIAID NIH HHS
  7. U19 AI135972/NIAID NIH HHS

MeSH Term

Active Transport, Cell Nucleus
Animals
Binding Sites
COVID-19
Chlorocebus aethiops
HEK293 Cells
Humans
Interferons
Nuclear Matrix-Associated Proteins
Nuclear Pore
Nuclear Pore Complex Proteins
Nucleocytoplasmic Transport Proteins
Protein Binding
STAT1 Transcription Factor
STAT2 Transcription Factor
Signal Transduction
Vero Cells
Viral Proteins

Chemicals

Nuclear Matrix-Associated Proteins
Nuclear Pore Complex Proteins
Nucleocytoplasmic Transport Proteins
Nup98 protein, human
ORF6 protein, SARS-CoV-2
RAE1 protein, human
STAT1 Transcription Factor
STAT1 protein, human
STAT2 Transcription Factor
STAT2 protein, human
Viral Proteins
Interferons
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.

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