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., …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