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

  • Proc Natl Acad Sci U S A. 2020 Nov 10;117(45):28344-28354. doi: 10.1073/pnas.2016650117.
Lisa Miorin  1  2 ,  Thomas Kehrer  3  2 ,  Maria Teresa Sanchez-Aparicio  3  2 ,  Ke Zhang  4 ,  Phillip Cohen  3 ,  Roosheel S Patel  3 ,  Anastasija Cupic  3  2 ,  Tadashi Makio  5 ,  Menghan Mei  6 ,  Elena Moreno  3  2 ,  Oded Danziger  3 ,  Kris M White  3  2 ,  Raveen Rathnasinghe  3  2 ,  Melissa Uccellini  3  2 ,  Shengyan Gao  4 ,  Teresa Aydillo  3  2 ,  Ignacio Mena  3  2 ,  Xin Yin  7 ,  Laura Martin-Sancho  7 ,  Nevan J Krogan  3  8  9  10 ,  Sumit K Chanda  7 ,  Michael Schotsaert  3  2 ,  Richard W Wozniak  5 ,  Yi Ren  6 ,  Brad R Rosenberg  3 ,  Beatriz M A Fontoura  4 ,  Adolfo García-Sastre  1  2  11  12
Affiliations
  • 1. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; [email protected] [email protected].
  • 2. Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  • 3. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  • 4. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • 5. Department of Cell Biology, University of Alberta, Edmonton, AB T6G 2H7, Canada.
  • 6. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232.
  • 7. Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
  • 8. Quantitative Biosciences Institute, University of California San Francisco, CA 94158.
  • 9. Gladstone Institute of Data Science and Biosciences, J. David Gladstone Institutes, San Francisco, CA 94158.
  • 10. Department of Cellular and Molecular Pharmacology, University of California San Francisco, CA 94143.
  • 11. Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  • 12. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
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.