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Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis.
Kehrer, Thomas; Cupic, Anastasija; Ye, Chengjin; Yildiz, Soner; Bouhaddou, Mehdi; Crossland, Nicholas A; Barrall, Erika A; Cohen, Phillip; Tseng, Anna; Çagatay, Tolga; Rathnasinghe, Raveen; Flores, Daniel; Jangra, Sonia; Alam, Fahmida; Mena, Ignacio; Aslam, Sadaf; Saqi, Anjali; Rutkowska, Magdalena; Ummadi, Manisha R; Pisanelli, Giuseppe; Richardson, R Blake; Veit, Ethan C; Fabius, Jacqueline M; Soucheray, Margaret; Polacco, Benjamin J; Ak, Baran; Marin, Arturo; Evans, Matthew J; Swaney, Danielle L; Gonzalez-Reiche, Ana S; Sordillo, Emilia M; van Bakel, Harm; Simon, Viviana; Zuliani-Alvarez, Lorena; Fontoura, Beatriz M A; Rosenberg, Brad R; Krogan, Nevan J; Martinez-Sobrido, Luis; García-Sastre, Adolfo; Miorin, Lisa.
Affiliation
  • Kehrer T; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Cupic A; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Ye C; Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
  • Yildiz S; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Bouhaddou M; QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, Universit
  • Crossland NA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02215, USA; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA.
  • Barrall EA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Cohen P; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Tseng A; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02215, USA; Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA.
  • Çagatay T; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Rathnasinghe R; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10
  • Flores D; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Jangra S; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Alam F; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Mena I; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Aslam S; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Saqi A; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
  • Rutkowska M; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Ummadi MR; QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, Universit
  • Pisanelli G; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Veterinary Medicine and Animal Production, University of Naples Federico II, 80137
  • Richardson RB; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Veit EC; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Fabius JM; QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA.
  • Soucheray M; QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, Universit
  • Polacco BJ; QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, Universit
  • Ak B; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Marin A; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Evans MJ; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Swaney DL; QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, Universit
  • Gonzalez-Reiche AS; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Sordillo EM; Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • van Bakel H; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Simon V; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount S
  • Zuliani-Alvarez L; QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, Universit
  • Fontoura BMA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Rosenberg BR; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Krogan NJ; QBI COVID-19 Research Group (QCRG), San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, Universit
  • Martinez-Sobrido L; Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
  • García-Sastre A; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount S
  • Miorin L; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: lisa.miorin@mssm.edu.
Cell Host Microbe ; 31(10): 1668-1684.e12, 2023 10 11.
Article in En | MEDLINE | ID: mdl-37738983
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.
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Full text: 1 Database: MEDLINE Main subject: Viral Proteins / SARS-CoV-2 / COVID-19 Type of study: Etiology_studies Limits: Humans Language: En Year: 2023 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Viral Proteins / SARS-CoV-2 / COVID-19 Type of study: Etiology_studies Limits: Humans Language: En Year: 2023 Type: Article