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.

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