|Bone marrow stromal cell antigen 2|
Rendering based on PDB .
|RNA expression pattern|
Tetherin also known as bone marrow stromal antigen 2 is a lipid raft associatedprotein that in humans is encoded by the BST2 gene.123 In addition, tetherin has been designated as CD317 (cluster of differentiation 317). This protein is constituitively expressed in mature B cells, plasma cells and plasmacytoid dendritic cells, and in many other cells, it is only expressed as a response to a stimuli from IFN pathway.4
Tetherin is part of IFN-dependent antiviral response pathway. When the presence of virus and viral components is detected by recognition molecules such as (RIG-I), a cascades of interactions happen between signaling molecules, eventually the signal reaches the nucleus to upregulate the expression of Interferon Stimulating Genes (ISGs), this in turn activates IFN-a pathway to send the signal to neighboring cells, which causes upregulation in the expression of other ISGs and many viral restriction factors, such as tetherin.56
Tetherin is a human cellular protein which inhibits retrovirus infection by preventing the diffusion of virus particles after budding from infected cells. Initially discovered as an inhibitor to HIV-1 infection in the absence of Vpu, tetherin has also been shown to inhibit the release of other viruses such as the Lassa and Marburg virions78 suggesting a common mechanism that inhibits enveloped virus release without interaction with viral proteins.
Tetherin is a type 2 integral membrane protein, with the N-terminus in the cytoplasm, one membrane spanning domain, and a C-terminus modified by the addition of a glycosyl-phosphatidylinositol (gpi) anchor.9 The transmembrane of tetherin is predicted to be a single alpha helix. The ectodomain consists of alpha helical coiled-coil region where the coils are slightly spread apart.10 Although Tetherin is localized to the lipid rafts on the surface of the cells, they are endocytosed to be sorted through TGN by clathrin-dependent pathway. This is mediated by AP2 binding to the dual-tyrosine motif located in the cytosolic domain of tetherin.3 When the virion buds from the surface of the cell, one of the tetherin membrane domains is in the new viral membrane, the other remains in the plasma membrane, tethering the virion to the cell. It is antagonized by the viral protein Vpu11 which is thought to work by targeting tetherin for degradation via the β-TrCP2 dependent pathway.1213
Tetherin exists as a dimer on the surface of cells, and prevention of dimerisation by mutating the cystine residues, prevents tetherin from inhibiting virus release, although it is still detectable in the cell. The stabilization of the protein through disulfide bond within the coiled coil region seems to be important in its function4
Tetherin is known to block many different types of enveloped viruses by tethering the budding virus like particles (VLPs) and inhibiting them from leaving the cell surface. Studies have shown that it is not the amino acid sequence, but the topology of tetherin is required for the tethering of virions on the cell surface.4 Their unique topology allows them to be in the cell through their N-terminus while using the GPI anchor to attach to budding virions.10 HIV-1 overcomes this restriction through vpu. Vpu interacts with tethrin by interacting with the protein at its transmembrane domain and recruiting β-TrCP2, which causes ubiquitination and degradation of tetherin. It has been recently shown that tetherin gene variants are associated with HIV disease progression underscoring the role of BST-2 in HIV type 1 infection.14 Another primate lentivirus, SIV, also, counteracts tetherin by their removal from the plasma membrane.1516 KSHV protein K5 also targets tetherin for degradation through ubiquitination.17 Ebola counteracts tethrin through two mechanism. VP35 of Ebola, inhibits multiple steps of IFN-signaling pathway, which blocks the induction of tetherin as a downstream effect. Also, it has been noted that the full-length Ebola GP may either translocate tetherin or disrupt the structure of tetherin.5 Sendai virus proteins HN and F direct tethrin to endosomes or proteasome for degradation.18 CHIKV protein nsP1 interacts with tetherin by disrupting the tetherin-virion complex formation.19
Cell-to-cell transmission through virological synapse in human retroviruses is also inhibited by tetherin. Tetherin aggregates virions and downmodulates the infectivity of the virions. It has also been suggested that tetherin may be involved in the structural integrity of the virological synapse.4
Tetherin has also been predicted to be involved in cell adhesion and cell migration. Recently it has, also, been identified as the protein that help stabilize lipid rafts by joining nearby lipid rafts to form a cluster.20 For some viruses, such as Dengue virus, tetherin inhibits the budding of virions as well as cell-to-cell transmission of the virus.21 Interestingly, for human cytomegalovirus (HCMV), tetherin promotes entry of the virus, especially during cell differentiation. It has also been shown that tetherin is incorporated into newly formed virions.22
- Ishikawa J, Kaisho T, Tomizawa H, Lee BO, Kobune Y, Inazawa J, Oritani K, Itoh M, Ochi T, Ishihara K, et al. (Aug 1995). "Molecular cloning and chromosomal mapping of a bone marrow stromal cell surface gene, BST2, that may be involved in pre-B-cell growth". Genomics 26 (3): 527–34. doi:10.1016/0888-7543(95)80171-H. PMID 7607676.
- "Entrez Gene: BST2 bone marrow stromal cell antigen 2".
- Rollason R, Korolchuk V, Hamilton C, Schu P, Banting G (November 2007). "Clathrin-mediated endocytosis of a lipid-raft-associated protein is mediated through a dual tyrosine motif". J. Cell. Sci. 120 (Pt 21): 3850–8. doi:10.1242/jcs.003343. PMID 17940069.
- Le Tortorec A, Willey S, Neil SJ (May 2011). "Antiviral inhibition of enveloped virus release by tetherin/BST-2: action and counteraction". Viruses 3 (5): 520–40. doi:10.3390/v3050520. PMC 3185764. PMID 21994744.
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- Douglas JL, Gustin JK, Viswanathan K, Mansouri M, Moses AV, Früh K (May 2010). "The great escape: viral strategies to counter BST-2/tetherin". PLoS Pathog. 6 (5): e1000913. doi:10.1371/journal.ppat.1000913. PMC 2869331. PMID 20485522.
- Sakuma T, Noda T, Urata S, Kawaoka Y, Yasuda J (March 2009). "Inhibition of Lassa and Marburg virus production by tetherin". J. Virol. 83 (5): 2382–5. doi:10.1128/JVI.01607-08. PMC 2643706. PMID 19091864.
- Thaczuk D (2008-02-11). "Tetherin: a newly discovered host cell protein that inhibits HIV replication". NAM AIDS Map.
- Andrew AJ, Miyagi E, Kao S, Strebel K (2009). "The formation of cysteine-linked dimers of BST-2/tetherin is important for inhibition of HIV-1 virus release but not for sensitivity to Vpu". Retrovirology 6: 80. doi:10.1186/1742-4690-6-80. PMC 2754425. PMID 19737401.
- Evans DT, Serra-Moreno R, Singh RK, Guatelli JC (September 2010). "BST-2/tetherin: a new component of the innate immune response to enveloped viruses". Trends Microbiol. 18 (9): 388–96. doi:10.1016/j.tim.2010.06.010. PMC 2956607. PMID 20688520.
- Neil SJ, Zang T, Bieniasz PD (January 2008). "Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu". Nature 451 (7177): 425–30. doi:10.1038/nature06553. PMID 18200009.
- Mangeat B, Gers-Huber G, Lehmann M, Zufferey M, Luban J, Piguet V (September 2009). "HIV-1 Vpu neutralizes the antiviral factor Tetherin/BST-2 by binding it and directing its beta-TrCP2-dependent degradation". PLoS Pathog. 5 (9): e1000574. doi:10.1371/journal.ppat.1000574. PMC 2729927. PMID 19730691.
- Iwabu Y, Fujita H, Kinomoto M, Kaneko K, Ishizaka Y, Tanaka Y, Sata T, Tokunaga K. (December 2009). "HIV-1 accessory protein Vpu internalizes cell-surface BST-2/tetherin through transmembrane interactions leading to lysosomes". J. Biol. Chem. 284 (50): 35060–72. doi:10.1074/jbc.M109.058305. PMC 2787367. PMID 19837671.
- Laplana M, Caruz A, Pineda JA, Puig T, Fibla J (February 2013). "Association of BST-2 gene variants with HIV disease progression underscores the role of BST-2 in HIV type 1 infection.". J Infect Dis 207 (3): 411–419. doi:10.1093/infdis/jis685. PMID 23148293.
- Jia B, Serra-Moreno R, Neidermyer W, Rahmberg A, Mackey J, Fofana IB, Johnson WE, Westmoreland S, Evans DT (May 2009). "Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2". PLoS Pathog. 5 (5): e1000429. doi:10.1371/journal.ppat.1000429. PMC 2673686. PMID 19436700.
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- Mansouri M, Viswanathan K, Douglas JL, Hines J, Gustin J, Moses AV, Früh K (October 2009). "Molecular mechanism of BST2/tetherin downregulation by K5/MIR2 of Kaposi's sarcoma-associated herpesvirus". J. Virol. 83 (19): 9672–81. doi:10.1128/JVI.00597-09. PMC 2748026. PMID 19605472.
- Bampi C, Rasga L, Roux L (March 2013). "Antagonism to human BST-2 / tetherin by Sendai virus glycoproteins". J. Gen. Virol. doi:10.1099/vir.0.051771-0. PMID 23468424.
- Jones PH, Maric M, Madison MN, Maury W, Roller RJ, Okeoma CM (March 2013). "BST-2/tetherin-mediated restriction of chikungunya (CHIKV) VLP budding is counteracted by CHIKV non-structural protein 1 (nsP1)". Virology 438 (1): 37–49. doi:10.1016/j.virol.2013.01.010. PMID 23411007.
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- Viswanathan K, Smith MS, Malouli D, Mansouri M, Nelson JA, Früh K (November 2011). "BST2/Tetherin enhances entry of human cytomegalovirus". PLoS Pathog. 7 (11): e1002332. doi:10.1371/journal.ppat.1002332. PMC 3207899. PMID 22072961.
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