| Structural highlights
Function
[BST2_MOUSE] IFN-induced antiviral host restriction factor which efficiently blocks the release of diverse mammalian enveloped viruses by directly tethering nascent virions to the membranes of infected cells. Acts as a direct physical tether, holding virions to the cell membrane and linking virions to each other. The tethered virions can be internalized by endocytosis and subsequently degraded or they can remain on the cell surface. In either case, their spread as cell-free virions is restricted. Its target viruses belong to diverse families, including retroviridae: human immunodeficiency virus type 1 (HIV-1), mouse mammary tumor virus (MMTV) and murine leukemia virus (MLV), filoviridae: ebola virus (EBOV), arenaviridae: lassa virus (LASV), and rhabdoviridae: vesicular stomatitis virus (VSV). Can inhibit cell surface proteolytic activity of MMP14 causing decreased activation of MMP15 which results in inhibition of cell growth and migration. Can stimulate signaling by LILRA4/ILT7 and consequently provide negative feedback to the production of IFN by plasmacytoid dendritic cells in response to viral infection. Plays a role in the organization of the subapical actin cytoskeleton in polarized epithelial cells.[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
BST-2/tetherin is a host anti-viral molecule that functions to potently inhibit the release of enveloped viruses from infected cells. In return, viruses have evolved antagonists to this activity. BST-2 traps budding virions by using two separate membrane-anchoring regions that simultaneously incorporate into the host and viral membrane. Here we detail the structural and biophysical properties of the full BST-2 ectodomain, which spans the two membrane anchors. The 1.6 Angstrom crystal structure of the complete mouse BST-2 ectodomain reveals a ~145 Angstrom parallel dimer in an extended alpha-helix conformation that predominantly forms a coiled-coil bridged by three intermolecular disulfides that are required for stability. Sequence analysis in the context of the structure reveals an evolutionarily conserved design that destabilizes the coiled-coil, resulting in a labile superstructure, as evidenced by solution X-ray scattering displaying bent conformations spanning 150 Angstrom and 180 Angstrom for mouse and human BST-2 ectodomains, respectively. Additionally, crystal packing analysis reveals possible curvature-sensing tetrameric structures that may aid in proper placement of BST-2 during the genesis of viral progeny. Overall, this extended coiled-coil structure with inherent plasticity is undoubtedly necessary to accommodate the dynamics of virus budding while ensuring separation of the anchors.
Structural and biophysical analysis of BST-2/tetherin ectodomains reveal an evolutionary conserved design to inhibit virus release.,Swiecki M, Scheaffer SM, Allaire M, Fremont DH, Colonna M, Brett TJ J Biol Chem. 2010 Nov 17. PMID:21084286[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Blasius AL, Giurisato E, Cella M, Schreiber RD, Shaw AS, Colonna M. Bone marrow stromal cell antigen 2 is a specific marker of type I IFN-producing cells in the naive mouse, but a promiscuous cell surface antigen following IFN stimulation. J Immunol. 2006 Sep 1;177(5):3260-5. PMID:16920966
- ↑ Kaletsky RL, Francica JR, Agrawal-Gamse C, Bates P. Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2886-91. doi:, 10.1073/pnas.0811014106. Epub 2009 Jan 28. PMID:19179289 doi:10.1073/pnas.0811014106
- ↑ Radoshitzky SR, Dong L, Chi X, Clester JC, Retterer C, Spurgers K, Kuhn JH, Sandwick S, Ruthel G, Kota K, Boltz D, Warren T, Kranzusch PJ, Whelan SP, Bavari S. Infectious Lassa virus, but not filoviruses, is restricted by BST-2/tetherin. J Virol. 2010 Oct;84(20):10569-80. doi: 10.1128/JVI.00103-10. Epub 2010 Aug 4. PMID:20686043 doi:10.1128/JVI.00103-10
- ↑ Goffinet C, Schmidt S, Kern C, Oberbremer L, Keppler OT. Endogenous CD317/Tetherin limits replication of HIV-1 and murine leukemia virus in rodent cells and is resistant to antagonists from primate viruses. J Virol. 2010 Nov;84(21):11374-84. doi: 10.1128/JVI.01067-10. Epub 2010 Aug 11. PMID:20702620 doi:http://dx.doi.org/10.1128/JVI.01067-10
- ↑ Sarojini S, Theofanis T, Reiss CS. Interferon-induced tetherin restricts vesicular stomatitis virus release in neurons. DNA Cell Biol. 2011 Dec;30(12):965-74. doi: 10.1089/dna.2011.1384. Epub 2011 Sep , 15. PMID:21919738 doi:http://dx.doi.org/10.1089/dna.2011.1384
- ↑ Liberatore RA, Bieniasz PD. Tetherin is a key effector of the antiretroviral activity of type I interferon in vitro and in vivo. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18097-101. doi:, 10.1073/pnas.1113694108. Epub 2011 Oct 24. PMID:22025715 doi:http://dx.doi.org/10.1073/pnas.1113694108
- ↑ Swiecki M, Wang Y, Gilfillan S, Lenschow DJ, Colonna M. Cutting edge: paradoxical roles of BST2/tetherin in promoting type I IFN response and viral infection. J Immunol. 2012 Mar 15;188(6):2488-92. doi: 10.4049/jimmunol.1103145. Epub 2012, Feb 10. PMID:22327075 doi:http://dx.doi.org/10.4049/jimmunol.1103145
- ↑ Jones PH, Mehta HV, Maric M, Roller RJ, Okeoma CM. Bone marrow stromal cell antigen 2 (BST-2) restricts mouse mammary tumor virus (MMTV) replication in vivo. Retrovirology. 2012 Jan 27;9:10. doi: 10.1186/1742-4690-9-10. PMID:22284121 doi:http://dx.doi.org/10.1186/1742-4690-9-10
- ↑ Swiecki M, Scheaffer SM, Allaire M, Fremont DH, Colonna M, Brett TJ. Structural and biophysical analysis of BST-2/tetherin ectodomains reveal an evolutionary conserved design to inhibit virus release. J Biol Chem. 2010 Nov 17. PMID:21084286 doi:10.1074/jbc.M110.190538
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