Journal articles: 'BST2/Tetherin'

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Ooi, Yaw, Mathieu Dubé, and Margaret Kielian. "BST2/Tetherin Inhibition of Alphavirus Exit." Viruses 7, no. 4 (April 22, 2015): 2147–67. http://dx.doi.org/10.3390/v7042147.

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Viswanathan, Kasinath, M. Shane Smith, Daniel Malouli, Mandana Mansouri, Jay A. Nelson, and Klaus Früh. "BST2/Tetherin Enhances Entry of Human Cytomegalovirus." PLoS Pathogens 7, no. 11 (November 3, 2011): e1002332. http://dx.doi.org/10.1371/journal.ppat.1002332.

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Shi, Yuhang, Sydney Simpson, Yuexuan Chen, Haley Aull, Jared Benjamin, and Ruth Serra-Moreno. "Mutations accumulated in the Spike of SARS-CoV-2 Omicron allow for more efficient counteraction of the restriction factor BST2/Tetherin." PLOS Pathogens 20, no. 1 (January 8, 2024): e1011912. http://dx.doi.org/10.1371/journal.ppat.1011912.

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BST2/Tetherin is a restriction factor with broad antiviral activity against enveloped viruses, including coronaviruses. Specifically, BST2 traps nascent particles to membrane compartments, preventing their release and spread. In turn, viruses have evolved multiple mechanisms to counteract BST2. Here, we examined the interactions between BST2 and SARS-CoV-2. Our study shows that BST2 reduces SARS-CoV-2 virion release. However, the virus uses the Spike (S) protein to downregulate BST2. This requires a physical interaction between S and BST2, which routes BST2 for lysosomal degradation in a Clathtin- and ubiquitination-dependent manner. By surveying different SARS-CoV-2 variants of concern (Alpha-Omicron), we found that Omicron is more efficient at counteracting BST2, and that mutations in S account for its enhanced anti-BST2 activity. Mapping analyses revealed that several surfaces in the extracellular region of BST2 are required for an interaction with the Spike, and that the Omicron variant has changed its patterns of association with BST2 to improve its counteraction. Therefore, our study suggests that, besides enhancing receptor binding and evasion of neutralizing antibodies, mutations accumulated in the Spike afford more efficient counteraction of BST2, which highlights that BST2 antagonism is important for SARS-CoV-2 infectivity and spread.

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Zheng, Yun, Xiangqi Hao, Qingxu Zheng, Xi Lin, Xin Zhang, Weijie Zeng, Shiyue Ding, Pei Zhou, and Shoujun Li. "Canine Influenza Virus is Mildly Restricted by Canine Tetherin Protein." Viruses 10, no. 10 (October 16, 2018): 565. http://dx.doi.org/10.3390/v10100565.

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Tetherin (BST2/CD317/HM1.24) has emerged as a key host-cell ·defence molecule that acts by inhibiting the release and spread of diverse enveloped virions from infected cells. We analysed the biological features of canine tetherin and found it to be an unstable hydrophilic type I transmembrane protein with one transmembrane domain, no signal peptide, and multiple glycosylation and phosphorylation sites. Furthermore, the tissue expression profile of canine tetherin revealed that it was particularly abundant in immune organs. The canine tetherin gene contains an interferon response element sequence that can be regulated and expressed by canine IFN-α. A CCK-8 assay showed that canine tetherin was effective in helping mitigate cellular damage caused by canine influenza virus (CIV) infection. Additionally, we found that the overexpression of canine tetherin inhibited replication of the CIV and that interference with the canine tetherin gene enhanced CIV replication in cells. The impact of canine tetherin on CIV replication was mild. However, these results elucidate the role of the innate immune factor, canine tetherin, during CIV infection for the first time.

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Mansouri, Mandana, Kasinath Viswanathan, Janet L. Douglas, Jennie Hines, Jean Gustin, Ashlee V. Moses, and Klaus Früh. "Molecular Mechanism of BST2/Tetherin Downregulation by K5/MIR2 of Kaposi's Sarcoma-Associated Herpesvirus." Journal of Virology 83, no. 19 (July 15, 2009): 9672–81. http://dx.doi.org/10.1128/jvi.00597-09.

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ABSTRACT K3/MIR1 and K5/MIR2 of Kaposi's sarcoma-associated herpesvirus (KSHV) are viral members of the membrane-associated RING-CH (MARCH) ubiquitin ligase family and contribute to viral immune evasion by directing the conjugation of ubiquitin to immunostimulatory transmembrane proteins. In a quantitative proteomic screen for novel host cell proteins downregulated by viral immunomodulators, we previously observed that K5, as well as the human immunodeficiency virus type 1 (HIV-1) immunomodulator VPU, reduced steady-state levels of bone marrow stromal cell antigen 2 (BST2; also called CD317 or tetherin), suggesting that BST2 might be a novel substrate of K5 and VPU. Recent work revealed that in the absence of VPU, HIV-1 virions are tethered to the plasma membrane in BST2-expressing HeLa cells. By targeting BST2, K5 might thus similarly overcome an innate antiviral host defense mechanism. Here we establish that despite its type II transmembrane topology and carboxy-terminal glycosylphosphatidylinositol (GPI) anchor, BST2 represents a bona fide target of K5 that is downregulated during primary infection by and reactivation of KSHV. Upon exit of the protein from the endoplasmic reticulum, lysines in the short amino-terminal domain of BST2 are ubiquitinated by K5, resulting in rapid degradation of BST2. Ubiquitination of BST2 is required for degradation, since BST2 lacking cytosolic lysines was K5 resistant and ubiquitin depletion by proteasome inhibitors restored BST2 surface expression. Thus, BST2 represents the first type II transmembrane protein targeted by K5 and the first example of a protein that is both ubiquitinated and GPI linked. We further demonstrate that KSHV release is decreased in the absence of K5 in a BST2-dependent manner, suggesting that K5 contributes to the evasion of intracellular antiviral defense programs.

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Kelly, James T., Stacey Human, Joseph Alderman, Fatoumatta Jobe, Leanne Logan, Thomas Rix, Daniel Gonçalves-Carneiro, et al. "BST2/Tetherin Overexpression Modulates Morbillivirus Glycoprotein Production to Inhibit Cell–Cell Fusion." Viruses 11, no. 8 (July 30, 2019): 692. http://dx.doi.org/10.3390/v11080692.

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The measles virus (MeV), a member of the genus Morbillivirus, is an established pathogen of humans. A key feature of morbilliviruses is their ability to spread by virus–cell and cell–cell fusion. The latter process, which leads to syncytia formation in vitro and in vivo, is driven by the viral fusion (F) and haemagglutinin (H) glycoproteins. In this study, we demonstrate that MeV glycoproteins are sensitive to inhibition by bone marrow stromal antigen 2 (BST2/Tetherin/CD317) proteins. BST2 overexpression causes a large reduction in MeV syncytia expansion. Using quantitative cell–cell fusion assays, immunolabeling, and biochemistry we further demonstrate that ectopically expressed BST2 directly inhibits MeV cell–cell fusion. This restriction is mediated by the targeting of the MeV H glycoprotein, but not other MeV proteins. Using truncation mutants, we further establish that the C-terminal glycosyl-phosphatidylinositol (GPI) anchor of BST2 is required for the restriction of MeV replication in vitro and cell–cell fusion. By extending our study to the ruminant morbillivirus peste des petits ruminants virus (PPRV) and its natural host, sheep, we also confirm this is a broad and cross-species specific phenotype.

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Zhao, Xiaojuan, Dominic Alibhai, Ting Sun, Jawad Khalil, James L. Hutchinson, Kaya Olzak, Christopher M. Williams, et al. "Tetherin/BST2, a physiologically and therapeutically relevant regulator of platelet receptor signalling." Blood Advances 5, no. 7 (April 1, 2021): 1884–98. http://dx.doi.org/10.1182/bloodadvances.2020003182.

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Abstract The reactivity of platelets, which play a key role in the pathogenesis of atherothrombosis, is tightly regulated. The integral membrane protein tetherin/bone marrow stromal antigen-2 (BST-2) regulates membrane organization, altering both lipid and protein distribution within the plasma membrane. Because membrane microdomains have an established role in platelet receptor biology, we sought to characterize the physiological relevance of tetherin/BST-2 in those cells. To characterize the potential importance of tetherin/BST-2 to platelet function, we used tetherin/BST-2−/− murine platelets. In the mice, we found enhanced function and signaling downstream of a subset of membrane microdomain–expressing receptors, including the P2Y12, TP thromboxane, thrombin, and GPVI receptors. Preliminary studies in humans have revealed that treatment with interferon-α (IFN-α), which upregulates platelet tetherin/BST-2 expression, also reduces adenosine diphosphate–stimulated platelet receptor function and reactivity. A more comprehensive understanding of how tetherin/BST-2 negatively regulates receptor function was provided in cell line experiments, where we focused on the therapeutically relevant P2Y12 receptor (P2Y12R). Tetherin/BST-2 expression reduced both P2Y12R activation and trafficking, which was accompanied by reduced receptor lateral mobility specifically within membrane microdomains. In fluorescence lifetime imaging-Förster resonance energy transfer (FLIM-FRET)–based experiments, agonist stimulation reduced basal association between P2Y12R and tetherin/BST-2. Notably, the glycosylphosphatidylinositol (GPI) anchor of tetherin/BST-2 was required for both receptor interaction and observed functional effects. In summary, we established, for the first time, a fundamental role of the ubiquitously expressed protein tetherin/BST-2 in negatively regulating membrane microdomain–expressed platelet receptor function.

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Miller, Katelyn D., Christine Matullo, Riley Williams, Carli B. Jones, and Glenn F. Rall. "Murine BST2/tetherin promotes measles virus infection of neurons." Virology 563 (November 2021): 38–43. http://dx.doi.org/10.1016/j.virol.2021.08.005.

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Dietrich, Isabelle, Margaret J. Hosie, and Brian J. Willett. "The role of BST2/tetherin in feline retrovirus infection." Veterinary Immunology and Immunopathology 143, no. 3-4 (October 2011): 255–64. http://dx.doi.org/10.1016/j.vetimm.2011.06.020.

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Vigan, Raphaël, and Stuart J. D. Neil. "Determinants of Tetherin Antagonism in the Transmembrane Domain of the Human Immunodeficiency Virus Type 1 Vpu Protein." Journal of Virology 84, no. 24 (October 6, 2010): 12958–70. http://dx.doi.org/10.1128/jvi.01699-10.

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ABSTRACT Tetherin (BST2/CD317) potently restricts the particle release of human immunodeficiency virus type 1 (HIV-1) mutants defective in the accessory gene vpu. Vpu antagonizes tetherin activity and induces its cell surface downregulation and degradation in a manner dependent on the transmembrane (TM) domains of both proteins. We have carried out extensive mutagenesis of the HIV-1 NL4.3 Vpu TM domain to identify three amino acid positions, A14, W22, and, to a lesser extent, A18, that are required for tetherin antagonism. Despite the mutants localizing indistinguishably from the wild-type (wt) protein and maintaining the ability to multimerize, mutation of these positions rendered Vpu incapable of coimmunoprecipitating tetherin or mediating its cell surface downregulation. Interestingly, these amino acid positions are predicted to form one face of the Vpu transmembrane alpha helix and therefore potentially contribute to an interacting surface with the transmembrane domain of tetherin either directly or by modulating the conformation of Vpu oligomers. While the equivalent of W22 is invariant in HIV-1/SIVcpz Vpu proteins, the positions of A14 and A18 are highly conserved among Vpu alleles from HIV-1 groups M and N, but not those from group O or SIVcpz that lack human tetherin (huTetherin)-antagonizing activity, suggesting that they may have contributed to the adaption of HIV-1 to human tetherin.

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Petit, Sarah J., Caroline Blondeau, and Greg J. Towers. "Analysis of the human immunodeficiency virus type 1 M group Vpu domains involved in antagonizing tetherin." Journal of General Virology 92, no. 12 (December 1, 2011): 2937–48. http://dx.doi.org/10.1099/vir.0.035931-0.

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Zoonosis of chimpanzee simian immunodeficiency virus cpz to humans has given rise to both pandemic (M) and non-pandemic (O, N and P) groups of human immunodeficiency virus type-1 (HIV). These lentiviruses encode accessory proteins, including Vpu, which has been shown to reduce CD4 levels on the cell surface, as well as increase virion release from the cell by antagonizing tetherin (CD317, BST2). Here, we confirm that O group Vpus (Ca9 and BCF06) are unable to counteract tetherin or downregulate the protein from the cell surface, although they are still able to reduce cell-surface CD4 levels. We hypothesize that this inability to antagonize tetherin may have contributed to O group viruses failing to achieve pandemic levels of human-to-human transmission. Characterization of chimeric O/M group Vpus and Vpu mutants demonstrate that the Vpu–tetherin interaction is complex, involving several domains. We identify specific residues within the transmembrane proximal region that, along with the transmembrane domain, are crucial for tetherin counteraction and enhanced virion release. We have also shown that the critical domains are responsible for the localization of M group Vpu to the trans-Golgi network, where it relocalizes tetherin to counteract its function. This work sheds light on the acquisition of anti-tetherin activity and the molecular details of pandemic HIV infection in humans.

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Sneha, Patil, Urmi Shah, and Seetharaman Balaji. "In Silico Insights into HIV-1 Vpu-Tetherin Interactions and Its Mutational Counterparts." Medical Sciences 7, no. 6 (June 22, 2019): 74. http://dx.doi.org/10.3390/medsci7060074.

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Tetherin, an interferon-induced host protein encoded by the bone marrow stromal antigen 2 (BST2/CD317/HM1.24) gene, is involved in obstructing the release of many retroviruses and other enveloped viruses by cross-linking the budding virus particles to the cell surface. This activity is antagonized in the case of human immunodeficiency virus (HIV)-1 wherein its accessory protein Viral Protein U (Vpu) interacts with tetherin, causing its downregulation from the cell surface. Vpu and tetherin connect through their transmembrane (TM) domains, culminating into events leading to tetherin degradation by recruitment of β-TrCP2. However, mutations in the TM domains of both proteins are reported to act as a resistance mechanism to Vpu countermeasure impacting tetherin’s sensitivity towards Vpu but retaining its antiviral activity. Our study illustrates the binding aspects of blood-derived, brain-derived, and consensus HIV-1 Vpu with tetherin through protein–protein docking. The analysis of the bound complexes confirms the blood-derived Vpu–tetherin complex to have the best binding affinity as compared to other two. The mutations in tetherin and Vpu are devised computationally and are subjected to protein–protein interactions. The complexes are tested for their binding affinities, residue connections, hydrophobic forces, and, finally, the effect of mutation on their interactions. The single point mutations in tetherin at positions L23Y, L24T, and P40T, and triple mutations at {L22S, F44Y, L37I} and {L23T, L37T, T45I}, while single point mutations in Vpu at positions A19H and W23Y and triplet of mutations at {V10K, A11L, A19T}, {V14T, I18T, I26S}, and {A11T, V14L, A15T} have revealed no polar contacts with minimal hydrophobic interactions between Vpu and tetherin, resulting in reduced binding affinity. Additionally, we have explored the aggregation potential of tetherin and its association with the brain-derived Vpu protein. This work is a possible step toward an understanding of Vpu–tetherin interactions.

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Arnaud, Frederick, Sarah G. Black, Lita Murphy, David J. Griffiths, Stuart J. Neil, Thomas E. Spencer, and Massimo Palmarini. "Interplay between Ovine Bone Marrow Stromal Cell Antigen 2/Tetherin and Endogenous Retroviruses." Journal of Virology 84, no. 9 (February 24, 2010): 4415–25. http://dx.doi.org/10.1128/jvi.00029-10.

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ABSTRACT Endogenous betaretroviruses (enJSRVs) of sheep are expressed abundantly in the female reproductive tract and play a crucial role in conceptus development and placental morphogenesis. Interestingly, the colonization of the sheep genome by enJSRVs is likely still ongoing. During early pregnancy, enJSRV expression correlates with the production of tau interferon (IFNT), a type I IFN, by the developing conceptus. IFNT is the pregnancy recognition signal in ruminants and possesses potent antiviral activity. In this study, we show that IFNT induces the expression of bone marrow stromal cell antigen 2 (BST2) (also termed CD317/tetherin) both in vitro and in vivo. The BST2 gene is duplicated in ruminants. Transfection assays found that ovine BST2 proteins (oBST2A and oBST2B) block release of viral particles produced by intact enJSRV loci and of related exogenous and pathogenic jaagsiekte sheep retrovirus (JSRV). Ovine BST2A appears to restrict enJSRVs more efficiently than oBST2B. In vivo, the expression of BST2A/B and enJSRVs in the endometrium increases after day 12 and remains high between days 14 and 20 of pregnancy. In situ hybridization analyses found that oBST2A is expressed mainly in the endometrial stromal cells but not in the luminal and glandular epithelial cells, in which enJSRVs are highly expressed. In conclusion, enJSRVs may have coevolved in the presence of oBST2A/B by being expressed in different cellular compartments of the same organ. Viral expression in cells unable to express BST2 may be one of the mechanisms used by retroviruses to escape restriction.

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Pan, Xiao-Ben, Jin-Chao Han, Xu Cong, and Lai Wei. "BST2/Tetherin Inhibits Dengue Virus Release from Human Hepatoma Cells." PLoS ONE 7, no. 12 (December 7, 2012): e51033. http://dx.doi.org/10.1371/journal.pone.0051033.

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Holmgren, Alicia M., Katelyn D. Miller, Sarah E. Cavanaugh, and Glenn F. Rall. "Bst2/Tetherin Is Induced in Neurons by Type I Interferon and Viral Infection but Is Dispensable for Protection against Neurotropic Viral Challenge." Journal of Virology 89, no. 21 (August 26, 2015): 11011–18. http://dx.doi.org/10.1128/jvi.01745-15.

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ABSTRACTIn permissive mouse central nervous system (CNS) neurons, measles virus (MV) spreads in the absence of hallmark viral budding or neuronal death, with transmission occurring efficiently and exclusively via the synapse. MV infection also initiates a robust type I interferon (IFN) response, resulting in the synthesis of a large number of genes, including bone marrow stromal antigen 2 (Bst2)/tetherin/CD317. Bst2 restricts the release of some enveloped viruses, but to date, its role in viral infection of neurons has not been assessed. Consequently, we investigated how Bst2 was induced and what role it played in MV neuronal infection. The magnitude of induction of neuronal Bst2 RNA and protein following IFN exposure and viral infection was notably higher than in similarly treated mouse embryo fibroblasts (MEFs). Bst2 synthesis was both IFN and Stat1 dependent. Although Bst2 prevented MV release from nonneuronal cells, its deletion had no effect on viral pathogenesis in MV-challenged mice. Our findings underscore how cell-type-specific differences impact viral infection and pathogenesis.IMPORTANCEViral infections of the central nervous system can lead to debilitating disease and death. Moreover, it is becoming increasingly clear that nonrenewable cells, including most central nervous system neurons, combat neurotropic viral infections in fundamentally different ways than other rapidly dividing and renewable cell populations. Here we identify type I interferon signaling as a key inducer of a known antiviral protein (Bst2) in neurons. Unexpectedly, the gene is dispensable for clearance of neurotropic viral infection despite its well-defined contribution to limiting the spread of enveloped viruses in proliferating cells. A deeper appreciation of the importance of cell type heterogeneity in antiviral immunity will aid in the identification of unique therapeutic targets for life-threatening viral infections.

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Petrosino, Maria, Francesco Stellato, Roberta Chiaraluce, Valerio Consalvi, Giovanni La Penna, Alessandra Pasquo, Olivier Proux, Giancarlo Rossi, and Silvia Morante. "Zn‐Induced Interactions Between SARS‐CoV‐2 orf7a and BST2/Tetherin." ChemistryOpen 10, no. 11 (November 2021): 1133–41. http://dx.doi.org/10.1002/open.202100217.

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Pan, Xiao-Ben, Xiao-Wang Qu, Dong Jiang, Xing-Liang Zhao, Jin-Chao Han, and Lai Wei. "BST2/Tetherin inhibits hepatitis C virus production in human hepatoma cells." Antiviral Research 98, no. 1 (April 2013): 54–60. http://dx.doi.org/10.1016/j.antiviral.2013.01.009.

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Bego, Mariana G., Lijun Cong, Katharina Mack, Frank Kirchhoff, and Éric A. Cohen. "Differential Control of BST2 Restriction and Plasmacytoid Dendritic Cell Antiviral Response by Antagonists Encoded by HIV-1 Group M and O Strains." Journal of Virology 90, no. 22 (August 31, 2016): 10236–46. http://dx.doi.org/10.1128/jvi.01131-16.

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ABSTRACT BST2/tetherin is a type I interferon (IFN-I)-stimulated host factor that restricts the release of HIV-1 by entrapping budding virions at the cell surface. This membrane-associated protein can also engage and activate the plasmacytoid dendritic cell (pDC)-specific immunoglobulin-like transcript 7 (ILT7) inhibitory receptor to downregulate the IFN-I response by pDCs. Pandemic HIV-1 group M uses Vpu (M-Vpu) to counteract the two BST2 isoforms (long and short) that are expressed in human cells. M-Vpu efficiently downregulates surface long BST2, while it displaces short BST2 molecules away from viral assembly sites. We recently found that this attribute is used by M-Vpu to activate the BST2/ILT7-dependent negative-feedback pathway and to suppress pDC IFN-I responses during sensing of infected cells. However, whether this property is conserved in endemic HIV-1 group O, which has evolved Nef (O-Nef) to counteract specifically the long BST2 isoform, remains unknown. In the present study, we validated that O-Nefs have the capacity to downregulate surface BST2 and enhance HIV-1 particle release although less efficiently than M-Vpu. In contrast to M-Vpu, O-Nef did not efficiently enhance viral spread in T cell culture or displace short BST2 from viral assembly sites to prevent its occlusion by tethered HIV-1 particles. Consequently, O-Nef impairs the ability of BST2 to activate negative ILT7 signaling to suppress the IFN-I response by pDC-containing peripheral blood mononuclear cells (PBMCs) during sensing of infected cells. These distinctive features of BST2 counteraction by O-Nefs may in part explain the limited spread of HIV-1 group O in the human population. IMPORTANCE The geographical distributions and prevalences of different HIV-1 groups show large variations. Understanding drivers of distinctive viral spread may aid in the development of therapeutic strategies for controlling the spread of HIV-1 pandemic strains. The differential spread of HIV-1 groups appears to be linked to their capacities to antagonize the long and short isoforms of the BST2 restriction factor. We found that the endemic HIV-1 group O-encoded BST2 antagonist Nef is unable to counteract the restriction mediated by short BST2, a condition that impairs its ability to activate ILT7 and suppress pDC antiviral responses. This is in contrast to the pandemic HIV-1 group M-specified BST2 countermeasure Vpu, which displays a diverse array of mechanisms to counteract short and long BST2 isoforms, an attribute that allows the effective control of pDC antiviral responses. These findings may help explain the limited spread of HIV-1 group O as well as the continued predominance of HIV-1 group M throughout the world.

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Strauss, Joshua D., Jason E. Hammonds, Hong Yi, Lingmei Ding, Paul Spearman, and Elizabeth R. Wright. "Three-Dimensional Structural Characterization of HIV-1 Tethered to Human Cells." Journal of Virology 90, no. 3 (November 18, 2015): 1507–21. http://dx.doi.org/10.1128/jvi.01880-15.

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ABSTRACTTetherin (BST2, CD317, or HM1.24) is a host cellular restriction factor that prevents the release of enveloped viruses by mechanically linking virions to the plasma membrane. The precise arrangement of tetherin molecules at the plasma membrane site of HIV-1 assembly, budding, and restriction is not well understood. To gain insight into the biophysical mechanism underlying tetherin-mediated restriction of HIV-1, we utilized cryo-electron tomography (cryo-ET) to directly visualize HIV-1 virus-like particles (VLPs) and virions tethered to human cells in three dimensions (3D). Rod-like densities that we refer to as tethers were seen connecting HIV-1 virions to each other and to the plasma membrane. Native immunogold labeling showed tetherin molecules located on HIV-1 VLPs and virions in positions similar to those of the densities observed by cryo-ET. The location of the tethers with respect to the ordered immature Gag lattice or mature conical core was random. However, tethers were not uniformly distributed on the viral membrane but rather formed clusters at sites of contact with the cell or other virions. Chains of tethered HIV-1 virions often were arranged in a linear fashion, primarily as single chains and, to a lesser degree, as branched chains. Distance measurements support the extended tetherin model, in which the coiled-coil ectodomains are oriented perpendicular with respect to the viral and plasma membranes.IMPORTANCETetherin is a cellular factor that restricts HIV-1 release by directly cross-linking the virus to the host cell plasma membrane. We used cryo-electron tomography to visualize HIV-1 tethered to human cells in 3D. We determined that tetherin-restricted HIV-1 virions were physically connected to each other or to the plasma membrane by filamentous tethers that resembled rods ∼15 nm in length, which is consistent with the extended tetherin model. In addition, we found the position of the tethers to be arbitrary relative to the ordered immature Gag lattice or the mature conical cores. However, when present as multiple copies, the tethers clustered at the interface between virions. Tethered HIV-1 virions were arranged in a linear fashion, with the majority as single chains. This study advances our understanding of tetherin-mediated HIV-1 restriction by defining the spatial arrangement and orientation of tetherin molecules at sites of HIV-1 restriction.

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Pan, X. B., J. H. Chang, T. M. Block, and J. T. Guo. "PP-145 BST2/Tetherin inhibits hepatitis C virus release from human hepatoma cells." International Journal of Infectious Diseases 15 (July 2011): S85—S86. http://dx.doi.org/10.1016/s1201-9712(11)60297-x.

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Presle, Adrien, Stéphane Frémont, Audrey Salles, Pierre-Henri Commere, Nathalie Sassoon, Clarisse Berlioz-Torrent, Neetu Gupta-Rossi, and Arnaud Echard. "The viral restriction factor tetherin/BST2 tethers cytokinetic midbody remnants to the cell surface." Current Biology 31, no. 10 (May 2021): 2203–13. http://dx.doi.org/10.1016/j.cub.2021.02.039.

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Sauter, Daniel, Michael Vogl, and Frank Kirchhoff. "Ancient origin of a deletion in human BST2/Tetherin that confers protection against viral zoonoses." Human Mutation 32, no. 11 (August 11, 2011): 1243–45. http://dx.doi.org/10.1002/humu.21571.

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Janvier, Katy, Nicolas Roy, and Clarisse Berlioz-Torrent. "Role of the Endosomal ESCRT Machinery in HIV-1 Vpu-Induced Down- Regulation of BST2/Tetherin." Current HIV Research 10, no. 4 (May 1, 2012): 315–20. http://dx.doi.org/10.2174/157016212800792414.

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Swiecki, Melissa, Yaming Wang, Susan Gilfillan, Deborah J. Lenschow, and Marco Colonna. "Cutting Edge: Paradoxical Roles of BST2/Tetherin in Promoting Type I IFN Response and Viral Infection." Journal of Immunology 188, no. 6 (February 10, 2012): 2488–92. http://dx.doi.org/10.4049/jimmunol.1103145.

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Schubert, H. L., Q. Zhai, V. Sandrin, D. M. Eckert, M. Garcia-Maya, L. Saul, W. I. Sundquist, R. A. Steiner, and C. P. Hill. "Structural and functional studies on the extracellular domain of BST2/tetherin in reduced and oxidized conformations." Proceedings of the National Academy of Sciences 107, no. 42 (September 29, 2010): 17951–56. http://dx.doi.org/10.1073/pnas.1008206107.

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Jia, Bin, Ruth Serra-Moreno, William Neidermyer, Andrew Rahmberg, John Mackey, Ismael Ben Fofana, Welkin E. Johnson, Susan Westmoreland, and David T. Evans. "Species-Specific Activity of SIV Nef and HIV-1 Vpu in Overcoming Restriction by Tetherin/BST2." PLoS Pathogens 5, no. 5 (May 15, 2009): e1000429. http://dx.doi.org/10.1371/journal.ppat.1000429.

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Epeldegui, Marta, Bianca Blom, and Christel H. Uittenbogaart. "BST2/Tetherin is constitutively expressed on human thymocytes with the phenotype and function of Treg cells." European Journal of Immunology 45, no. 3 (December 16, 2014): 728–37. http://dx.doi.org/10.1002/eji.201444787.

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Santos, Rodrigo I., Philipp A. Ilinykh, Colette A. Pietzsch, Adam J. Ronk, Kai Huang, Natalia A. Kuzmina, Fuchun Zhou, James E. Crowe, and Alexander Bukreyev. "Blocking of ebolavirus spread through intercellular connections by an MPER-specific antibody depends on BST2/tetherin." Cell Reports 42, no. 10 (October 2023): 113254. http://dx.doi.org/10.1016/j.celrep.2023.113254.

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Matatall, Katie A., Hamilton Wang, Roman Jaksik, Marek Kimmel, Dongsu Park, and Katherine Y. King. "A Novel Role for Bst2 and E-Selectin in IFNg-Stimulated HSC Niche Relocalization." Blood 132, Supplement 1 (November 29, 2018): 874. http://dx.doi.org/10.1182/blood-2018-99-116547.

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Abstract Prolonged exposure to proinflammatory conditions, such as during chronic infection, can lead to the development of bone marrow failure syndromes including aplastic anemia. Indeed, we have previously shown that chronic infection activates hematopoietic stem cells (HSCs), ultimately leading to bone marrow suppression due to an IFNgamma (IFNγ)-dependent depletion of HSCs. Defining the mechanisms behind inflammation mediated HSC loss may provide important insight into how inflammation affects hematopoiesis in many clinical conditions including infection, ageing, and myelodysplastic syndrome. HSC quiescence is maintained in large part through interactions with the surrounding cells of the bone marrow niche. In particular, HSCs closely colocalize with perivascular stromal cells that secrete high levels of the chemokine Cxcl12 and other hematopoietic maintenance factors such as angiopoietin, IL7, and stem cell factor. We hypothesized that IFNγ-induced activation may affect the positioning of HSCs relative to supporting cells within the bone marrow microenvironment. We used 3-D intravital imaging to assess the localization of HSCs relative to Cxcl12-abundant reticulocytes (CAR cells). When CMTMR-stained HSCs were transplanted into Cxcl12-GFP mice we found that IFNγ treatment led to a distancing of HSCs away from quiescence-enforcing CAR cells. In contrast, TNF-alpha treatment, which does not induce HSC proliferation at the concentration used, resulted in no such relocalization. Furthermore, no displacement occurred in response to IFNγ treatment when Ifngr1-deficient HSCs were transplanted, suggesting a cell-autonomous mechanism of relocalization. RNA expression analysis and chemotaxis assays showed that IFNγ-treated HSCs are not impaired in their ability to respond to Cxcl12 signaling, indicating that a change in Cxcl12-Cxcr4 interactions does not account for the movement of HSCs away from CAR cells. To further assess HSC-specific changes that may account for IFNγ-dependent relocalization, we performed gene expression analysis of HSCs from control or IFNγ-treated mice. We saw no change in the expression of common HSCs receptors that are thought to play a role in maintaining HSC quiescence, such as cKit, Cdh2, Mpl, Itgb1, Itbg2, Itga4, and Itga1. However, the surface protein, Bst2, also known as tetherin, was significantly upregulated in HSCs upon IFNγ stimulation. This was confirmed at both the RNA and protein level. A prior report identified Bst2 as a noncanonical E-selectin ligand. This finding is particularly interesting given that HSCs found in close proximity to E-selectin-expressing endothelial cells exist in an activated, proliferative state. Furthermore, the interaction between HSCs and E-selectin+ endothelial cells was previously noted to be independent of canonical E-selectin ligands such as Psgl1, CD44, or the Lewis family antigens. Thus we hypothesized that IFNγ-induced upregulation of surface Bst2 may facilitate proliferation by promoting HSC binding to E-selectin. Indeed, in vitro E-selectin binding assays showed that IFNγ treatment increased binding of progenitor cells to E-selectin, but not to the closely related adhesin, P-selectin. Inflammation plays an important role in the development of many cancers including acute myeloid leukemia (AML), leading us to investigate if Bst2 upregulation is an important factor in AML biology. Indeed, we found that increased levels of Bst2 are associated with poor survival in AML patients. Further, murine studies have shown that leukemic blasts have greatly increased E-selectin binding capacity following transformation. Using two independent AML cell lines, we found that IFNγ treatment upregulates Bst2 expression and increases E-selectin binding capacity. These findings suggest a mechanism by which inflammation could drive cell proliferation in AML. In summary, we have uncovered a potential new mechanism for IFNγ-induced HSC activation, whereby HSCs are relocalized in a Bst2-dependent manner from the quiescence-enforcing CAR niche to an active E-selectin-positive niche. Furthermore, we demonstrate that IFNγ-mediated Bst2 expression also occurs in AML, suggesting a mechanistic link between inflammation and AML progression. This study may open up new potential therapeutic avenues for the treatment of patients with chronic infection, inflammatory diseases, and cancer. Disclosures No relevant conflicts of interest to declare.

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Jaguva Vasudevan, Ananda Ayyappan, Daniel Becker, Tom Luedde, Holger Gohlke, and Carsten Münk. "Foamy Viruses, Bet, and APOBEC3 Restriction." Viruses 13, no. 3 (March 18, 2021): 504. http://dx.doi.org/10.3390/v13030504.

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Non-human primates (NHP) are an important source of viruses that can spillover to humans and, after adaptation, spread through the host population. Whereas HIV-1 and HTLV-1 emerged as retroviral pathogens in humans, a unique class of retroviruses called foamy viruses (FV) with zoonotic potential are occasionally detected in bushmeat hunters or zookeepers. Various FVs are endemic in numerous mammalian natural hosts, such as primates, felines, bovines, and equines, and other animals, but not in humans. They are apathogenic, and significant differences exist between the viral life cycles of FV and other retroviruses. Importantly, FVs replicate in the presence of many well-defined retroviral restriction factors such as TRIM5α, BST2 (Tetherin), MX2, and APOBEC3 (A3). While the interaction of A3s with HIV-1 is well studied, the escape mechanisms of FVs from restriction by A3 is much less explored. Here we review the current knowledge of FV biology, host restriction factors, and FV–host interactions with an emphasis on the consequences of FV regulatory protein Bet binding to A3s and outline crucial open questions for future studies.

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Hammonds, Jason, Jaang-Jiun Wang, Hong Yi, and Paul Spearman. "Immunoelectron Microscopic Evidence for Tetherin/BST2 as the Physical Bridge between HIV-1 Virions and the Plasma Membrane." PLoS Pathogens 6, no. 2 (February 5, 2010): e1000749. http://dx.doi.org/10.1371/journal.ppat.1000749.

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Paliwal, Daizy, Prashant Joshi, and Subrat Kumar Panda. "Hepatitis E Virus (HEV) egress: Role of BST2 (Tetherin) and interferon induced long non- coding RNA (lncRNA) BISPR." PLOS ONE 12, no. 11 (November 1, 2017): e0187334. http://dx.doi.org/10.1371/journal.pone.0187334.

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Sayeed, Aejaz, Gloria Luciani-Torres, Zhenhang Meng, James L. Bennington, Dan H. Moore, and Shanaz H. Dairkee. "Aberrant Regulation of the BST2 (Tetherin) Promoter Enhances Cell Proliferation and Apoptosis Evasion in High Grade Breast Cancer Cells." PLoS ONE 8, no. 6 (June 20, 2013): e67191. http://dx.doi.org/10.1371/journal.pone.0067191.

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Gustin, Jean K., Ying Bai, Ashlee V. Moses, and Janet L. Douglas. "Ebola Virus Glycoprotein Promotes Enhanced Viral Egress by Preventing Ebola VP40 From Associating With the Host Restriction Factor BST2/Tetherin." Journal of Infectious Diseases 212, suppl 2 (March 27, 2015): S181—S190. http://dx.doi.org/10.1093/infdis/jiv125.

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Madjo, Ursula, Olivier Leymarie, Stéphane Frémont, Aurelia Kuster, Mélanie Nehlich, Sarah Gallois-Montbrun, Katy Janvier, and Clarisse Berlioz-Torrent. "LC3C Contributes to Vpu-Mediated Antagonism of BST2/Tetherin Restriction on HIV-1 Release through a Non-canonical Autophagy Pathway." Cell Reports 17, no. 9 (November 2016): 2221–33. http://dx.doi.org/10.1016/j.celrep.2016.10.045.

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Pham, T. N. Q., S. Lukhele, and É. A. Cohen. "OA2-4 Enhancing HIV-1 virion tethering by BST2/tetherin sensitizes productively and latently infected T cells to ADCC mediated by broadly neutralizing anti-HIV antibodies." Journal of Virus Eradication 2 (July 2016): 3. http://dx.doi.org/10.1016/s2055-6640(20)31011-6.

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Mwimanzi, Philip, Ian Tietjen, Scott C. Miller, Aniqa Shahid, Kyle Cobarrubias, Natalie N. Kinloch, Bemuluyigza Baraki, et al. "Novel Acylguanidine-Based Inhibitor of HIV-1." Journal of Virology 90, no. 20 (August 10, 2016): 9495–508. http://dx.doi.org/10.1128/jvi.01107-16.

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ABSTRACTThe emergence of transmissible HIV-1 strains with resistance to antiretroviral drugs highlights a continual need for new therapies. Here we describe a novel acylguanidine-containing compound, 1-(2-(azepan-1-yl)nicotinoyl)guanidine (or SM111), that inhibitsin vitroreplication of HIV-1, including strains resistant to licensed protease, reverse transcriptase, and integrase inhibitors, without major cellular toxicity. At inhibitory concentrations, intracellular p24Gagproduction was unaffected, but virion release (measured as extracellular p24Gag) was reduced and virion infectivity was substantially impaired, suggesting that SM111 acts at a late stage of viral replication. SM111-mediated inhibition of HIV-1 was partially overcome by a Vpu I17R mutation alone or a Vpu W22* truncation in combination with Env N136Y. These mutations enhanced virion infectivity and Env expression on the surface of infected cells in the absence and presence of SM111 but also impaired Vpu's ability to downregulate CD4 and BST2/tetherin. Taken together, our results support acylguanidines as a class of HIV-1 inhibitors with a distinct mechanism of action compared to that of licensed antiretrovirals. Further research on SM111 and similar compounds may help to elucidate knowledge gaps related to Vpu's role in promoting viral egress and infectivity.IMPORTANCENew inhibitors of HIV-1 replication may be useful as therapeutics to counteract drug resistance and as reagents to perform more detailed studies of viral pathogenesis. SM111 is a small molecule that blocks the replication of wild-type and drug-resistant HIV-1 strains by impairing viral release and substantially reducing virion infectivity, most likely through its ability to prevent Env expression at the infected cell surface. Partial resistance to SM111 is mediated by mutations in Vpu and/or Env, suggesting that the compound affects host/viral protein interactions that are important during viral egress. Further characterization of SM111 and similar compounds may allow more detailed pharmacological studies of HIV-1 egress and provide opportunities to develop new treatments for HIV-1.

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Murphy, Lita, Mariana Varela, Sophie Desloire, Najate Ftaich, Claudio Murgia, Matthew Golder, Stuart Neil, et al. "The Sheep Tetherin Paralog oBST2B Blocks Envelope Glycoprotein Incorporation into Nascent Retroviral Virions." Journal of Virology 89, no. 1 (October 22, 2014): 535–44. http://dx.doi.org/10.1128/jvi.02751-14.

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ABSTRACTBone marrow stromal cell antigen 2 (BST2) is a cellular restriction factor with a broad antiviral activity. In sheep, theBST2gene is duplicated into two paralogs termedoBST2AandoBST2B. oBST2A impedes viral exit of the Jaagsiekte sheep retroviruses (JSRV), most probably by retaining virions at the cell membrane, similar to the “tethering” mechanism exerted by human BST2. In this study, we provide evidence that unlike oBST2A, oBST2B is limited to the Golgi apparatus and disrupts JSRV envelope (Env) trafficking by sequestering it. In turn, oBST2B leads to a reduction in Env incorporation into viral particles, which ultimately results in the release of virions that are less infectious. Furthermore, the activity of oBST2B does not seem to be restricted to retroviruses, as it also acts on vesicular stomatitis virus glycoproteins. Therefore, we suggest that oBST2B exerts antiviral activity using a mechanism distinct from the classical tethering restriction observed for oBST2A.IMPORTANCEBST2 is a powerful cellular restriction factor against a wide range of enveloped viruses. Sheep possess two paralogs of theBST2gene calledoBST2AandoBST2B. JSRV, the causative agent of a transmissible lung cancer of sheep, is known to be restricted by oBST2A. In this study, we show that unlike oBST2A, oBST2B impairs the normal cellular trafficking of JSRV envelope glycoproteins by sequestering them within the Golgi apparatus. We also show that oBST2B decreases the incorporation of envelope glycoprotein into JSRV viral particles, which in turn reduces virion infectivity. In conclusion, oBST2B exerts a novel antiviral activity that is distinct from those of BST2 proteins of other species.

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Tanwattana, Nathiphat, Nanchaya Wanasen, Yuparat Jantraphakorn, Kanjana Srisutthisamphan, Thanathom Chailungkarn, Suwimon Boonrungsiman, Boonlert Lumlertdacha, Porntippa Lekchareonsuk, and Challika Kaewborisuth. "Human BST2 inhibits rabies virus release independently of cysteine-linked dimerization and asparagine-linked glycosylation." PLOS ONE 18, no. 11 (November 3, 2023): e0292833. http://dx.doi.org/10.1371/journal.pone.0292833.

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The innate immune response is a first-line defense mechanism triggered by rabies virus (RABV). Interferon (IFN) signaling and ISG products have been shown to confer resistance to RABV at various stages of the virus’s life cycle. Human tetherin, also known as bone marrow stromal cell antigen 2 (hBST2), is a multifunctional transmembrane glycoprotein induced by IFN that has been shown to effectively counteract many viruses through diverse mechanisms. Here, we demonstrate that hBST2 inhibits RABV budding by tethering new virions to the cell surface. It was observed that release of virus-like particles (VLPs) formed by RABV G (RABV-G VLPs), but not RABV M (RABV-G VLPs), were suppressed by hBST2, indicating that RABV-G has a specific effect on the hBST2-mediated restriction of RABV. The ability of hBST2 to prevent the release of RABV-G VLPs and impede RABV growth kinetics is retained even when hBST2 has mutations at dimerization and/or glycosylation sites, making hBST2 an antagonist to RABV, with multiple mechanisms possibly contributing to the hBST2-mediated suppression of RABV. Our findings expand the knowledge of host antiviral mechanisms that control RABV infection.

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Zhao, Yifei, Ke Zhao, Shaohua Wang, and Juan Du. "Multi-functional BST2/tetherin against HIV-1, other viruses and LINE-1." Frontiers in Cellular and Infection Microbiology 12 (September 13, 2022). http://dx.doi.org/10.3389/fcimb.2022.979091.

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Bone marrow stromal cell antigen 2 (BST2), also known as CD317, HM1.24, or tetherin, is a type II transmembrane glycoprotein. Its expression is induced by IFN-I, and it initiates host immune responses by directly trapping enveloped HIV-1 particles onto the cell surface. This antagonistic mechanism toward the virus is attributable to the unique structure of BST2. In addition to its antiviral activity, BST2 restricts retrotransposon LINE-1 through a distinct mechanism. As counteractive measures, different viruses use a variety of proteins to neutralize the function or even stability of BST2. Interestingly, BST2 seems to have both a positive and a negative influence on immunomodulation and virus propagation. Here, we review the relationship between the structural and functional bases of BST2 in anti-HIV-1 and suppressing retrotransposon LINE-1 activation and focus on its dual features in immunomodulation and regulating virus propagation.

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Jia, Xiaofei, Erin Weber, Andrey Tokarev, Mary Lewinski, Maryan Rizk, Marissa Suarez, John Guatelli, and Yong Xiong. "Structural basis of HIV-1 Vpu-mediated BST2 antagonism via hijacking of the clathrin adaptor protein complex 1." eLife 3 (April 29, 2014). http://dx.doi.org/10.7554/elife.02362.

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BST2/tetherin, an antiviral restriction factor, inhibits the release of enveloped viruses from the cell surface. Human immunodeficiency virus-1 (HIV-1) antagonizes BST2 through viral protein u (Vpu), which downregulates BST2 from the cell surface. We report the crystal structure of a protein complex containing Vpu and BST2 cytoplasmic domains and the core of the clathrin adaptor protein complex 1 (AP1). This, together with our biochemical and functional validations, reveals how Vpu hijacks the AP1-dependent membrane trafficking pathways to mistraffick BST2. Vpu mimics a canonical acidic dileucine-sorting motif to bind AP1 in the cytosol, while simultaneously interacting with BST2 in the membrane. These interactions enable Vpu to build on an intrinsic interaction between BST2 and AP1, presumably causing the observed retention of BST2 in juxtanuclear endosomes and stimulating its degradation in lysosomes. The ability of Vpu to hijack AP-dependent trafficking pathways suggests a potential common theme for Vpu-mediated downregulation of host proteins.

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Judith, Delphine, Margaux Versapuech, Fabienne Bejjani, Marjory Palaric, Pauline Verlhac, Aurelia Kuster, Leslie Lepont, Sarah Gallois-Montbrun, Katy Janvier, and Clarisse Berlioz-Torrent. "ATG5 selectively engages virus-tethered BST2/tetherin in an LC3C-associated pathway." Proceedings of the National Academy of Sciences 120, no. 20 (May 8, 2023). http://dx.doi.org/10.1073/pnas.2217451120.

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Bone marrow stromal antigen 2 (BST2)/tetherin is a restriction factor that reduces HIV-1 dissemination by tethering virus at the cell surface. BST2 also acts as a sensor of HIV-1 budding, establishing a cellular antiviral state. The HIV-1 Vpu protein antagonizes BST2 antiviral functions via multiple mechanisms, including the subversion of an LC3C-associated pathway, a key cell intrinsic antimicrobial mechanism. Here, we describe the first step of this viral-induced LC3C-associated process. This process is initiated at the plasma membrane through the recognition and internalization of virus-tethered BST2 by ATG5, an autophagy protein. ATG5 and BST2 assemble as a complex, independently of the viral protein Vpu and ahead of the recruitment of the ATG protein LC3C. The conjugation of ATG5 with ATG12 is dispensable for this interaction. ATG5 recognizes cysteine-linked homodimerized BST2 and specifically engages phosphorylated BST2 tethering viruses at the plasma membrane, in an LC3C-associated pathway. We also found that this LC3C-associated pathway is used by Vpu to attenuate the inflammatory responses mediated by virion retention. Overall, we highlight that by targeting BST2 tethering viruses, ATG5 acts as a signaling scaffold to trigger an LC3C-associated pathway induced by HIV-1 infection.

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Dolskiy, Alexander A., Sergei A. Bodnev, Anastasia A. Nazarenko, Anastasia M. Smirnova, Olga G. Pyankova, Anna K. Matveeva, Irina V. Grishchenko, et al. "Deletion of BST2 Cytoplasmic and Transmembrane N-Terminal Domains Results in SARS-CoV, SARS-CoV-2, and Influenza Virus Production Suppression in a Vero Cell Line." Frontiers in Molecular Biosciences 7 (December 18, 2020). http://dx.doi.org/10.3389/fmolb.2020.616798.

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SARS-CoV-2, which emerged in Wuhan (China), has become a great worldwide problem in 2020 and has led to more than 1,000,000 deaths worldwide. Many laboratories are searching for ways to fight this pandemic. We studied the action of the cellular antiviral protein tetherin, which is encoded by the BST2 gene. We deleted the transmembrane domain-encoding part of the gene in the Vero cell line. The transmembrane domain is a target for virus-antagonizing proteins. We showed a decrease in SARS-CoV-2 in cells with deleted transmembrane BST2 domains compared to the initial Vero cell line. Similar results were obtained for SARS-CoV and avian influenza virus. This finding may help the development of antiviral therapies competitively targeting the transmembrane domain of tetherin with viral-antagonizing proteins.

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Botticelli, S., R. Chiaraluce, V. Consalvi, G. La Penna, A. Pasquo, M. Petrosino, O. Proux, G. C. Rossi, F. Stellato, and S. Morante. "The role of Zn ions in the interaction between SARS-CoV-2 orf7a protein and BST2/tetherin." European Physical Journal Plus 138, no. 3 (March 8, 2023). http://dx.doi.org/10.1140/epjp/s13360-023-03731-w.

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AbstractIn this paper, we provide evidence that Zn$$^{2+}$$ 2 + ions play a role in the SARS-CoV-2 virus strategy to escape the immune response mediated by the BST2-tetherin host protein. This conclusion is based on sequence analysis and molecular dynamics simulations as well as X-ray absorption experiments [1].

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Liberatore, Rachel A., Emily J. Mastrocola, Chelsea Powell, and Paul D. Bieniasz. "Tetherin Inhibits Cell-Free Virus Dissemination and Retards Murine Leukemia Virus Pathogenesis." Journal of Virology 91, no. 12 (April 5, 2017). http://dx.doi.org/10.1128/jvi.02286-16.

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ABSTRACT The relative contributions of cell-free virion circulation and direct cell-to-cell transmission to retroviral dissemination and pathogenesis are unknown. Tetherin/Bst2 is an antiviral protein that blocks enveloped virion release into the extracellular milieu but may not inhibit cell-to-cell virus transmission. We developed live-cell imaging assays which show that tetherin does not affect Moloney murine leukemia virus (MoMLV) spread, and only minimally affects vesicular stomatitis virus (VSV) spread, to adjacent cells in a monolayer. Conversely, cell-free MLV and VSV virion yields and VSV spread to distal cells were dramatically reduced by tetherin. To elucidate the roles of tetherin and cell-free virions during in vivo viral dissemination and pathogenesis, we developed mice carrying an inducible human tetherin (hTetherin) transgene. While ubiquitous hTetherin expression was detrimental to the growth and survival of mice, restriction of hTetherin expression to hematopoietic cells gave apparently healthy mice. The expression of hTetherin in hematopoietic cells had little or no effect on the number of MoMLV-infected splenocytes and thymocytes. However, hTetherin expression significantly reduced cell-free plasma viremia and also delayed MoMLV-induced disease. Overall, these results suggest that MoMLV spread within hematopoietic tissues and cell monolayers involves cell-to-cell transmission that is resistant to tetherin but that virion dissemination via plasma is inhibited by tetherin and is required for full MoMLV pathogenesis. IMPORTANCE Retroviruses are thought to spread primarily via direct cell-to-cell transmission, yet many have evolved to counteract an antiviral protein called tetherin, which may selectively inhibit cell-free virus release. We generated a mouse model with an inducible tetherin transgene in order to study how tetherin affects retroviral dissemination and on which cell types its expression is required to do so. We first developed a novel in vitro live-cell imaging assay to demonstrate that while tetherin does indeed dramatically reduce cell-free virus spreading, it has little to no effect on direct cell-to-cell transmission of either vesicular stomatitis virus (VSV) or the retrovirus MoMLV. Using our transgenic mouse model, we found that tetherin expression on hematopoietic cells resulted in the specific reduction of MoMLV cell-free plasma viremia but not the number of infected hematopoietic cells. The delay in disease associated with this scenario suggests a role for cell-free virus in retroviral disease progression.

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Rizk, Maryan G., Christopher F. Basler, and John Guatelli. "Cooperation of the Ebola Virus Proteins VP40 and GP1,2 with BST2 To Activate NF-κB Independently of Virus-Like Particle Trapping." Journal of Virology 91, no. 22 (September 6, 2017). http://dx.doi.org/10.1128/jvi.01308-17.

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ABSTRACT BST2 is a host protein with dual functions in response to viral infections: it traps newly assembled enveloped virions at the plasma membrane in infected cells, and it induces NF-κB activity, especially in the context of retroviral assembly. In this study, we examined whether Ebola virus proteins affect BST2-mediated induction of NF-κB. We found that the Ebola virus matrix protein, VP40, and envelope glycoprotein, GP, each cooperate with BST2 to induce NF-κB activity, with maximal activity when all three proteins are expressed. Unlike human immunodeficiency virus type 1 Vpu protein, which antagonizes both virion entrapment and the activation of NF-κB by BST2, Ebola virus GP does not inhibit NF-κB signaling even while it antagonizes the entrapment of virus-like particles. GP from Reston ebolavirus, a nonpathogenic species in humans, showed a phenotype similar to that of GP from Zaire ebolavirus, a highly pathogenic species, in terms of both the activation of NF-κB and the antagonism of virion entrapment. Although Ebola virus VP40 and GP both activate NF-κB independently of BST2, VP40 is the more potent activator. Activation of NF-κB by the Ebola virus proteins either alone or together with BST2 requires the canonical NF-κB signaling pathway. Mechanistically, the maximal NF-κB activation by GP, VP40, and BST2 together requires the ectodomain cysteines needed for BST2 dimerization, the putative BST2 tetramerization residue L70, and Y6 of a potential hemi-ITAM motif in BST2's cytoplasmic domain. BST2 with a glycosylphosphatidylinositol (GPI) anchor signal deletion, which is not expressed at the plasma membrane and is unable to entrap virions, activated NF-κB in concert with the Ebola virus proteins at least as effectively as wild-type BST2. Signaling by the GPI anchor mutant also depended on Y6 of BST2. Overall, our data show that activation of NF-κB by BST2 is independent of virion entrapment in the case of Ebola virus. Nonetheless, BST2 may induce or amplify proinflammatory signaling during Ebola virus infection, potentially contributing to the dysregulated cytokine response that is a hallmark of Ebola virus disease. IMPORTANCE Understanding how the host responds to viral infections informs the development of therapeutics and vaccines. We asked how proinflammatory signaling by the host protein BST2/tetherin, which is mediated by the transcription factor NF-κB, responds to Ebola virus proteins. Although the Ebola virus envelope glycoprotein (GP1,2) antagonizes the trapping of newly formed virions at the plasma membrane by BST2, we found that it does not inhibit BST2's ability to induce NF-κB activity. This distinguishes GP1,2 from the HIV-1 protein Vpu, the prototype BST2 antagonist, which inhibits both virion entrapment and the induction of NF-κB activity. Ebola virus GP1,2, the Ebola virus matrix protein VP40, and BST2 are at least additive with respect to the induction of NF-κB activity. The effects of these proteins converge on an intracellular signaling pathway that depends on a protein modification termed neddylation. Better mechanistic understanding of these phenomena could provide targets for therapies that modulate the inflammatory response during Ebola virus disease.

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Barriocanal, Marina, Elena Carnero, Victor Segura, and Puri Fortes. "Long Non-Coding RNA BST2/BISPR is Induced by IFN and Regulates the Expression of the Antiviral Factor Tetherin." Frontiers in Immunology 5 (January 9, 2015). http://dx.doi.org/10.3389/fimmu.2014.00655.

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OhAinle, Molly, Louisa Helms, Jolien Vermeire, Ferdinand Roesch, Daryl Humes, Ryan Basom, Jeffrey J. Delrow, Julie Overbaugh, and Michael Emerman. "A virus-packageable CRISPR screen identifies host factors mediating interferon inhibition of HIV." eLife 7 (December 6, 2018). http://dx.doi.org/10.7554/elife.39823.

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Interferon (IFN) inhibits HIV replication by inducing antiviral effectors. To comprehensively identify IFN-induced HIV restriction factors, we assembled a CRISPR sgRNA library of Interferon Stimulated Genes (ISGs) into a modified lentiviral vector that allows for packaging of sgRNA-encoding genomes in trans into budding HIV-1 particles. We observed that knockout of Zinc Antiviral Protein (ZAP) improved the performance of the screen due to ZAP-mediated inhibition of the vector. A small panel of IFN-induced HIV restriction factors, including MxB, IFITM1, Tetherin/BST2 and TRIM5alpha together explain the inhibitory effects of IFN on the CXCR4-tropic HIV-1 strain, HIV-1LAI, in THP-1 cells. A second screen with a CCR5-tropic primary strain, HIV-1Q23.BG505, described an overlapping, but non-identical, panel of restriction factors. Further, this screen also identifies HIV dependency factors. The ability of IFN-induced restriction factors to inhibit HIV strains to replicate in human cells suggests that these human restriction factors are incompletely antagonized.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see <xref ref-type="decision-letter" rid="SA1">decision letter</xref>).

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Shi, Yuhang, Sergio Castro-Gonzalez, Yuexuan Chen, and Ruth Serra-Moreno. "Effects of the SUMO Ligase BCA2 on Metabolic Activity, Cell Proliferation, Cell Migration, Cell Cycle, and the Regulation of NF-κB and IRF1 in Different Breast Epithelial Cellular Contexts." Frontiers in Cell and Developmental Biology 9 (September 13, 2021). http://dx.doi.org/10.3389/fcell.2021.711481.

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Breast cancer-associated gene 2 (BCA2) is an E3 ubiquitin and SUMO ligase with antiviral properties against HIV. Specifically, BCA2 (i) enhances the restriction imposed by BST2/Tetherin, impeding viral release; (ii) promotes the ubiquitination and degradation of the HIV protein Gag, limiting virion production; (iii) down-regulates NF-κB, which is necessary for HIV RNA synthesis; and (iv) activates the innate transcription factor IRF1. Due to its antiviral properties, ectopic expression of BCA2 in infected cells represents a promising therapeutic approach against HIV infection. However, BCA2 up-regulation is often observed in breast tumors. To date, the studies about BCA2 and cancer development are controversial, stating both pro- and anti-oncogenic roles. Here, we investigated the impact of BCA2 on cellular metabolic activity, cell proliferation, cell migration, and cell cycle progression. In addition, we also examined the ability of BCA2 to regulate NF-κB and IRF1 in transformed and non-tumor breast epithelial environments. Despite the fact that BCA2 promotes the transition from G1 to S phase of the cell cycle, it did not increase cell proliferation, migration nor metabolic activity. As expected, BCA2 maintains its enzymatic function at inhibiting NF-κB in different breast cancer cell lines. However, the effect of BCA2 on IRF1 differs depending on the cellular context. Specifically, BCA2 activates IRF1 in ER+ breast cell lines while it inhibits this transcription factor in ER– breast cancer cells. We hypothesize that the distinct actions of BCA2 over IRF1 may explain, at least in part, the different proposed roles for BCA2 in these cancers.

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Journal articles on the topic 'BST2/Tetherin'

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