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 (PubMed:22520941, PubMed:21529378, PubMed:20940320, PubMed:20419159, PubMed:20399176, PubMed:19879838, PubMed:19036818, PubMed:18342597, PubMed:18200009). Its target viruses belong to diverse families, including retroviridae: human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), simian immunodeficiency viruses (SIVs), equine infectious anemia virus (EIAV), feline immunodeficiency virus (FIV), prototype foamy virus (PFV), Mason-Pfizer monkey virus (MPMV), human T-cell leukemia virus type 1 (HTLV-1), Rous sarcoma virus (RSV) and murine leukemia virus (MLV), flavivirideae: hepatitis C virus (HCV), filoviridae: ebola virus (EBOV) and marburg virus (MARV), arenaviridae: lassa virus (LASV) and machupo virus (MACV), herpesviridae: kaposis sarcoma-associated herpesvirus (KSHV), rhabdoviridae: vesicular stomatitis virus (VSV), orthomyxoviridae: influenza A virus, paramyxoviridae: nipah virus, and coronaviridae: SARS-CoV (PubMed:22520941, PubMed:21621240, PubMed:21529378, PubMed:20943977, PubMed:20686043, PubMed:20419159, PubMed:20399176, PubMed:19879838, PubMed:19179289, PubMed:18342597, PubMed:18200009, PubMed:26378163, PubMed:31199522). Can inhibit cell surface proteolytic activity of MMP14 causing decreased activation of MMP15 which results in inhibition of cell growth and migration (PubMed:22065321). 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 (PubMed:19564354, PubMed:26172439). Plays a role in the organization of the subapical actin cytoskeleton in polarized epithelial cells. Isoform 1 and isoform 2 are both effective viral restriction factors but have differing antiviral and signaling activities (PubMed:23028328, PubMed:26172439). Isoform 2 is resistant to HIV-1 Vpu-mediated degradation and restricts HIV-1 viral budding in the presence of Vpu (PubMed:23028328, PubMed:26172439). Isoform 1 acts as an activator of NF-kappa-B and this activity is inhibited by isoform 2 (PubMed:23028328). Parallel homodimer; disulfide-linked. May form homotetramers under reducing conditions. Isoform 1 and isoform 2 form homodimers and also heterodimers with each other. Dimerization is essential for its antiviral activity (PubMed:26378163, PubMed:10329429, PubMed:19737401, PubMed:19879838, PubMed:23028328, PubMed:20399176, PubMed:20880831, PubMed:20940320, PubMed:31199522). Interacts (via cytoplasmic domain) with ARHGAP44 (By similarity). Interacts with MMP14 (via C-terminal cytoplasmic tail) (PubMed:22065321). Interacts with LILRA4/ILT7 (PubMed:19564354). (Microbial infection) Interacts with ebola GP protein. (Microbial infection) Interacts (via transmembrane domain) with HIV-1 VPU (via transmembrane domain). (Microbial infection) Interacts with HIV-2 ENV. (Microbial infection) Interacts with SARS-CoV ORF7a protein. Shuttles between the cell membrane, where it is present predominantly in membrane/lipid rafts, and the trans-Golgi network. Forms a complex with MMP14 and localizes to the cytoplasm. (Microbial infection) HIV-1 VPU and HIV-2 ENV can target it to the trans-Golgi network thus sequestering it away from virus assembly sites on the cell membrane. Targeted to late endosomes upon KSHV infection and subsequent ubiquitination. Predominantly expressed in liver, lung, heart and placenta. Lower levels in pancreas, kidney, skeletal muscle and brain. Overexpressed in multiple myeloma cells. Highly expressed during B-cell development, from pro-B precursors to plasma cells. Highly expressed on T-cells, monocytes, NK cells and dendritic cells (at protein level). By type I interferons. (Microbial infection) Down-regulated by HIV-1 VPU protein. Antagonizes its function by targeting it to the trans-Golgi network, sequestering it away from virus assembly sites on the cell membrane. VPU also acts as an adapter molecule linking it to BTRC, a substrate recognition subunit of the Skp1/Cullin/F-box protein E3 ubiquitin ligase, inducing its ubiquitination and subsequent proteasomal degradation. (Microbial infection) Down-regulated by HIV-2 ENV protein. Antagonizes its function by targeting it to the trans-Golgi network, sequestering it away from virus assembly sites on the cell membrane. (Microbial infection) Down-regulated by KSHV K5 protein. K5 ubiquitinates it leading to its targeting to late endosomes and degradation. (Microbial infection) Down-regulated by ebola virus GP protein. (Microbial infection) Made inactive by SARS-CoV ORF7a protein through impairing proper glycosylation (PubMed:26378163). May be down-regulated by SARS-CoV Spike protein through lysosomal degradation pathway (PubMed:31199522). The extracellular coiled coil domain forms an extended 170 A long semi-flexible rod-like structure important for virion retention at the cell surface and prevention of virus spreading. Monoubiquitinated by KSHV E3 ubiquitin-protein ligase K5, leading to its targeting to late endosomes and degradation. The GPI anchor is essential for its antiviral activity. Tetherin shows evidence of positive (adaptive) selection, presumably as a result of evolutionary pressure applied by antagonistic viral proteins that counteract its inhibitiory activity and this has led to the species-specific tetherin sensitivity to viral countermeasures. For example, Tantalus monkey tetherin cannot be abrogated by HIV-1 VPU due to variation in the tetherin transmembrane region. Similarly, SIV Nefs are able to overcome simian tetherins, but not human tetherin, due to a unique 5-amino-acid deletion in the cytoplasmic tail domain of human tetherin (PubMed:19917491). Produced by alternative initiation at Met-13 of isoform 1. Belongs to the tetherin family.