Tetherin

Tetherin, also known as  bone marrow stromal antigen 2, is a lipid raft associated is_associated_with::protein that in humans is encoded by the BST2 is_associated_with::gene. In addition, tetherin has been designated as CD317 (is_associated_with::cluster of differentiation 317). This protein is constitutively expressed in mature B cells, plasma cells and plasmacytoid dendritic cells, and in many other cells, it is only expressed as a response to stimuli from IFN pathway.

Gene activation
Tetherin is part of is_associated_with::IFN-dependent antiviral response pathway. When the presence of virus and viral components is detected by recognition molecules such as (is_associated_with::RIG-I), a cascades of interactions happen between signaling molecules, eventually the signal reaches the nucleus to upregulate the expression of is_associated_with::interferon-stimulated 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.

Function
Tetherin is a human cellular protein which inhibits is_associated_with::retrovirus infection by preventing the diffusion of virus particles after budding from infected cells. Initially discovered as an inhibitor to is_associated_with::HIV-1 infection in the absence of is_associated_with::Vpu, tetherin has also been shown to inhibit the release of other viruses such as the Lassa and Marburg virions suggesting a common mechanism that inhibits enveloped virus release without interaction with viral proteins.

Structure
Tetherin is a type 2 integral membrane protein, with the is_associated_with::N-terminus in the is_associated_with::cytoplasm, one membrane spanning domain, and a is_associated_with::C-terminus modified by the addition of a is_associated_with::glycosyl-phosphatidylinositol (gpi) anchor. The transmembrane of tetherin is predicted to be a single alpha helix. The ectodomain consists of alpha helical is_associated_with::coiled-coil region where the coils are slightly spread apart. 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. 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 is_associated_with::Vpu which is thought to work by targeting tetherin for degradation via the β-TrCP2 dependent pathway.

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 is_associated_with::disulfide bond within the is_associated_with::coiled coil region seems to be important in its function

Interaction with different viruses
Tetherin is known to block many different types of enveloped viruses by tethering the budding virus like particles (is_associated_with::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. Their unique topology allows them to be in the cell through their N-terminus while using the GPI anchor to attach to budding virions. HIV-1 overcomes this restriction through vpu. is_associated_with::Vpu interacts with tethrin by interacting with the protein at its transmembrane domain and recruiting β-TrCP2, which causes is_associated_with::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. Another primate lentivirus, SIV, also, counteracts tetherin by their removal from the plasma membrane. KSHV protein K5 also targets tetherin for degradation through ubiquitination. 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. Sendai virus proteins HN and F direct tethrin to endosomes or proteasome for degradation. CHIKV protein nsP1 interacts with tetherin by disrupting the tetherin-virion complex formation.

Cell-to-cell transmission through is_associated_with::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 is_associated_with::virological synapse.

Other functions
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. For some viruses, such as is_associated_with::Dengue virus, tetherin inhibits the budding of virions as well as cell-to-cell transmission of the virus. Interestingly, for human cytomegalovirus (is_associated_with::HCMV), tetherin promotes entry of the virus, especially during cell differentiation. It has also been shown that tetherin is incorporated into newly formed virions.