Alternative titles; symbols
HGNC Approved Gene Symbol: BST2
Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38): 19:17,402,939-17,405,630 (from NCBI)
BST2 is an apical cell surface protein that links cholesterol-rich lipid rafts to the actin network via association with RICH2 (617716), EBP50 (SLC9A3R1; 604990), and ezrin (123900) (Rollason et al., 2009).
Bone marrow stromal cells regulate B-cell growth and development through their surface molecules and cytokines. Ishikawa et al. (1995) produced a monoclonal antibody that recognized a novel human membrane protein, BST2, which is expressed on bone marrow stromal cell lines and rheumatoid arthritis synovial cell lines. They cloned a cDNA encoding CST2 and showed that it is a 30- to 36-kD type II transmembrane protein consisting of 180 amino acids. BST2 is expressed not only on certain bone marrow stromal cell lines but also on various normal tissues, although its expression pattern is different from that of BST1 (600387).
By comparative sequence analysis, Cocka and Bates (2012) identified alternative translation initiation sites in human BST2 that generate long and short tetherin isoforms. The short isoform lacks 12 N-terminal residues present in the long isoform. Western blot and immunoprecipitation analyses showed that the long and short tetherin isoforms assembled into homo- and heterodimers.
Ishikawa et al. (1995) localized the BST2 gene to chromosome 19p13.2 by fluorescence in situ hybridization.
Ishikawa et al. (1995) found that BST2 surface expression on fibroblast cell lines facilitated the stromal cell-dependent growth of a murine bone marrow-derived pre-B-cell line. The results suggested that BST2 may be involved in pre-B-cell growth.
Human cells possess an antiviral activity that inhibits the release of retrovirus particles, and other enveloped virus particles, and is antagonized by the HIV-1 accessory protein, Vpu. This antiviral activity can be constitutively expressed or induced by interferon-alpha (147660), and it consists of protein-based tethers, which Neil et al. (2008) termed 'tetherins,' that cause retention of fully-formed virions on infected cell surfaces. Using deductive constraints and gene expression analyses, Neil et al. (2008) identified CD317 (also called BST2 or HM1.24), a membrane protein of previously unknown function, as a tetherin. Specifically, CD317 expression correlated with, and induced, a requirement for Vpu during HIV-1 and murine leukemia virus particle release. Furthermore, in cells where HIV-1 virion release requires Vpu expression, depletion of CD317 abolished this requirement. CD317 caused retention of virions on cell surfaces, and after endocytosis, in CD317-positive compartments. Neil et al. (2008) suggested that inhibition of Vpu function and consequent mobilization of tetherin's antiviral activity is a potential therapeutic strategy in HIV/AIDS.
With extended time in culture, confluent human Caco-2 colon carcinoma cells differentiate into tall and highly polarized monolayers similar to intestinal epithelial cells. Rollason et al. (2009) found that the majority of CD317 was intracellular in nonpolarized Caco-2 cells; in contrast, CD317 predominantly localized to the apical membrane in fully differentiated Caco-2 cells. Knockdown of CD317 via short interfering RNA reduced the height of fully differentiated Caco-2 cells, reduced the number and length of microvilli, increased the amount of active RAC (RACGAP1; 604980) and RHO (RHOA; 165390), and rearranged the actin cytoskeleton, but had no effect on formation and function of tight junctions or localization of apical and basolateral markers. Protein interaction assays revealed that the N-terminal domain of CD317 binds EBP50 and a C-terminal region of RICH2, providing a link between CD317 and ezrin at the actin cytoskeleton. Knockdown of RICH2 in Caco-2 cells phenocopied knockdown of CD317. Rollason et al. (2009) noted that CD317 constitutively cycles between the cell surface and an intracellular compartment in nonpolarized cells, and that internalization of cell-surface CD317 is mediated by the interaction of the cytosolic domain of CD317 with the subunits of the AP2 adaptor complex. RICH2 interacts with the same region of the CD317 cytosolic domain that is recognized by AP2, suggesting that RICH2 masks AP2-binding sites on CD317 and inhibits CD317 internalization in fully differentiated Caco-2 cells.
Using several cell systems, Kuhl et al. (2010) found that tetherin, but not CAML (CAMLG; 601118), restricted Vpu-mediated retroviral release in HIV-1 nonpermissive cells.
Sauter et al. (2010) reviewed the structure and function of tetherin, as well as its role as a restriction factor that blocks the release of HIV-1 and other enveloped viruses.
Cocka and Bates (2012) found that, in response to HIV-1 Vpu, surface expression of the long tetherin isoform was downregulated more than that of the short isoform, and they observed preferential degradation of the long form. Mutation of serine and threonine residues in the 12-amino acid unique region of the long isoform resulted in resistance to Vpu-mediated degradation. Luciferase analysis indicated that the long isoform, but not the short isoform, induced NFKB (see 164011) activation. The short isoform was found to inhibit activation mediated by the long isoform. Cocka and Bates (2012) concluded that the presence of 2 tetherin isoforms provides mechanisms for control of tetherin antiviral and signaling functions in the presence or absence of infection.
Sauter et al. (2011) noted that the major (M) strain of HIV-1 has effectively spread in humans through its evasion of 3 human antiretroviral factors: TRIM5 (608487), APOBEC3G (607113), and BST2. Human BST2 provides a barrier to infection with chimpanzee and gorilla simian immunodeficiency viruses (SIVs), the direct precursors of HIV-1, due to a deletion of 5 amino acids (DIWKK in chimp and AILKK in gorilla) in the BST2 cytoplasmic domain that confers resistance to the SIV Nef protein. In addition, the human BST2 protein has a glu instead of an asp preceding the deleted sequence. To counteract BST2, the M strain of HIV-1 switched from Nef to Vpu. Sauter et al. (2011) found that the BST2 deletion was present in 2 archaic human groups, Neanderthals and Siberian Denisovans, which split from modern humans about 804,000 years ago. Humans and chimps diverged about 6.4 million years ago, suggesting that the deletion occurred 1 to 6 million years ago. Sauter et al. (2011) concluded that while the human BST2 barrier is not insurmountable, as the M strain of HIV-1 demonstrates, it appears difficult for primate lentiviruses and other primate viruses to overcome it. They suggested that the finding that the deletion in BST2 evolved more than 800,000 years ago may explain the rarity of successful transmission and spread of these agents among humans.
Cocka, L. J., Bates, P. Identification of alternatively translated tetherin isoforms with differing antiviral and signaling activities. PLoS Pathog. 8: e1002931, 2012. Note: Electronic Article. [PubMed: 23028328] [Full Text: https://doi.org/10.1371/journal.ppat.1002931]
Ishikawa, J., Kaisho, T., Tomizawa, H., Lee, B. O., Kobune, Y., Inazawa, J., Oritani, K., Itoh, M., Ochi, T., Ishihara, K., Hirano, T. 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: 527-534, 1995. [PubMed: 7607676] [Full Text: https://doi.org/10.1016/0888-7543(95)80171-h]
Kuhl, A., Munch, J., Sauter, D., Bertram, S., Glowacka, I., Steffen, I., Sprecht, A., Hofmann, H., Schneider, H., Behrens, G., Pohlmann, S. Calcium-modulating cyclophilin ligand does not restrict retrovirus release. (Letter) Nature Med. 16: 155-157, 2010. [PubMed: 20134461] [Full Text: https://doi.org/10.1038/nm0210-155]
Neil, S. J. D., Zang, T., Bieniasz, P. D. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451: 425-430, 2008. [PubMed: 18200009] [Full Text: https://doi.org/10.1038/nature06553]
Rollason, R., Korolchuk, V., Hamilton, C., Jepson, M., Banting, G. A CD317/tetherin-RICH2 complex plays a critical role in the organization of the subapical actin cytoskeleton in polarized epithelial cells. J. Cell Biol. 184: 721-736, 2009. [PubMed: 19273615] [Full Text: https://doi.org/10.1083/jcb.200804154]
Sauter, D., Specht, A., Kirchhoff, F. Tetherin: holding on and letting go. Cell 141: 392-398, 2010. [PubMed: 20434978] [Full Text: https://doi.org/10.1016/j.cell.2010.04.022]
Sauter, D., Vogl, M., Kirchhoff, F. Ancient origin of a deletion in human BST2/Tetherin that confers protection against viral zoonoses. Hum. Mutat. 32: 1243-1245, 2011. [PubMed: 21796732] [Full Text: https://doi.org/10.1002/humu.21571]