2. Academic Validation
  3. Severe Acute Respiratory Syndrome Coronavirus ORF7a Inhibits Bone Marrow Stromal Antigen 2 Virion Tethering through a Novel Mechanism of Glycosylation Interference

Severe Acute Respiratory Syndrome Coronavirus ORF7a Inhibits Bone Marrow Stromal Antigen 2 Virion Tethering through a Novel Mechanism of Glycosylation Interference

  • J Virol. 2015 Dec;89(23):11820-33. doi: 10.1128/JVI.02274-15.
Justin K Taylor 1,  Christopher M Coleman 1,  Sandra Postel 2,  Jeanne M Sisk 1,  John G Bernbaum 3,  Thiagarajan Venkataraman 1,  Eric J Sundberg 4,  Matthew B Frieman 5
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, University of Maryland at Baltimore, Baltimore, Maryland, USA.
  • 2 Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
  • 3 Integrated Research Facility, National Institutes of Health, Frederick, Maryland, USA.
  • 4 Department of Microbiology and Immunology, University of Maryland at Baltimore, Baltimore, Maryland, USA Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
  • 5 Department of Microbiology and Immunology, University of Maryland at Baltimore, Baltimore, Maryland, USA mfrieman@som.umaryland.edu.
PMID: 26378163 DOI: 10.1128/JVI.02274-15
Abstract

Severe acute respiratory syndrome (SARS) emerged in November 2002 as a case of atypical pneumonia in China, and the causative agent of SARS was identified to be a novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV). Bone marrow stromal antigen 2 (BST-2; also known as CD317 or tetherin) was initially identified to be a pre-B-cell growth promoter, but it also inhibits the release of virions of the retrovirus human immunodeficiency virus type 1 (HIV-1) by tethering budding virions to the host cell membrane. Further work has shown that BST-2 restricts the release of many Other viruses, including the human coronavirus 229E (hCoV-229E), and the genomes of many of these viruses encode BST-2 antagonists to overcome BST-2 restriction. Given the previous studies on BST-2, we aimed to determine if BST-2 has the ability to restrict SARS-CoV and if the SARS-CoV genome encodes any proteins that modulate BST-2's Antiviral function. Through an in vitro screen, we identified four potential BST-2 modulators encoded by the SARS-CoV genome: the papain-like protease (PLPro), nonstructural protein 1 (nsp1), ORF6, and ORF7a. As the function of ORF7a in SARS-CoV replication was previously unknown, we focused our study on ORF7a. We found that BST-2 does restrict SARS-CoV, but the loss of ORF7a leads to a much greater restriction, confirming the role of ORF7a as an inhibitor of BST-2. We further characterized the mechanism of BST-2 inhibition by ORF7a and found that ORF7a localization changes when BST-2 is overexpressed and ORF7a binds directly to BST-2. Finally, we also show that SARS-CoV ORF7a blocks the restriction activity of BST-2 by blocking the glycosylation of BST-2.

Importance: The severe acute respiratory syndrome coronavirus (SARS-CoV) emerged from zoonotic sources in 2002 and caused over 8,000 infections and 800 deaths in 37 countries around the world. Identifying host factors that regulate SARS-CoV pathogenesis is critical to understanding how this lethal virus causes disease. We have found that BST-2 is capable of restricting SARS-CoV release from cells; however, we also identified a SARS-CoV protein that inhibits BST-2 function. We show that the SARS-CoV protein ORF7a inhibits BST-2 glycosylation, leading to a loss of BST-2's Antiviral function.

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