Tetherin

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-stimulated genes (ISGs), this in turn activates IFN-α 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. Tetherin/BST2 and BST1 genes are unregulated by the Nicotinamide (NAM) metabolism pathway. == Function ==

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 RNA viruses such as the Lassa and Marburg virions suggesting a common mechanism that inhibits enveloped virus release without interaction with viral proteins. In addition, tetherin also restricts neuroinvasion of the DNA virus HSV-1. However, in contrast to its anti-viral role, it has recently been shown that basal levels of BST2 or Tetherin are required for HIV-1 replication but this isn't an indication that higher than basal levels of BST2 promotes viral replication. More definite research is required. Beyond viral particles, BST2 (CD317) may also tether native cellular membrane components to the cell surface, including extracellular vesicles or exosomes, thereby limiting their release and diffusion to other cells. By restricting the spread of such vesicles, BST2 could influence intercellular communication and signaling in physiological and pathological contexts. == Structure ==

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. 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. 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. 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 disulfide bond within the 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 (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. 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. CHIKV protein nsP1 interacts with tetherin by disrupting the tetherin-virion complex formation. 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. == Tetherin as a biomarker and other functions ==

Tetherin has been shown as a Type-I-IFN biomarker using flow cytometry, B cell Tetherin was used as a Cell-Specific Assay for Response to Type I Interferon Predicts Clinical Features and Flares in Systemic Lupus Erythematosus. 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 Dengue virus, tetherin inhibits the budding of virions as well as cell-to-cell transmission of the virus. 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. Tetherin expression has also been reported to be rapidly induced on the surface of hematopoietic stem cells following challenge with viral-like (poly-Inosinic-poly-Cytidylic acid) or bacterial-like (Lipopolysaccharide) immune stimuli. It was found that tetherin expression marked entry of quiescent hematopoietic stem cells into cell cycle following these stimulation. == References ==