Severe acute respiratory syndrome coronavirus ORF7a inhibits bone marrow stromal antigen 2 virion tethering through a novel mechanism of glycosylation interference

Taylor, Justin K.; Coleman, Christopher M.; Postel, Sandra; Sisk, Jeanne M.; Bernbaum, John G.; Venkataraman, Thiagarajan; Sundberg, Eric J.; Frieman, Matthew B.

Abstract

© 2015, American Society for Microbiology. 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 SARSCoV ORF7a blocks the restriction activity of BST-2 by blocking the glycosylation of BST-2.

Citation

Taylor, J. K., Coleman, C. M., Postel, S., Sisk, J. M., Bernbaum, J. G., Venkataraman, T., Sundberg, E. J., & Frieman, M. B. (2015). Severe acute respiratory syndrome coronavirus ORF7a inhibits bone marrow stromal antigen 2 virion tethering through a novel mechanism of glycosylation interference. Journal of Virology, 89(23), 11820-11833. https://doi.org/10.1128/JVI.02274-15

• Journal Article Type: Article
• Acceptance Date: Sep 4, 2015
• Online Publication Date: Sep 16, 2015
• Publication Date: Dec 1, 2015
• Deposit Date: Dec 17, 2019
• Journal: Journal of Virology
• Print ISSN: 0022-538X
• Electronic ISSN: 1098-5514
• Publisher: American Society for Microbiology
• Peer Reviewed: Peer Reviewed
• Volume: 89
• Issue: 23
• Pages: 11820-11833
• DOI: https://doi.org/10.1128/JVI.02274-15
• Public URL: https://nottingham-repository.worktribe.com/output/3590095