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.{{cite journal | vauthors = Kühl A, Pöhlmann S | title = How Ebola virus counters the interferon system | journal = Zoonoses and Public Health | volume = 59 | issue = Suppl 2 | pages = 116–131 | date = September 2012 | pmid = 22958256 | pmc = 7165950 | doi = 10.1111/j.1863-2378.2012.01454.x }}{{cite journal | vauthors = Douglas JL, Gustin JK, Viswanathan K, Mansouri M, Moses AV, Früh K | title = The great escape: viral strategies to counter BST-2/tetherin | journal = PLOS Pathogens | volume = 6 | issue = 5 | pages = e1000913 | date = May 2010 | pmid = 20485522 | pmc = 2869331 | doi = 10.1371/journal.ppat.1000913 | doi-access = free }}{{cite journal | vauthors = Neil SJ, Zang T, Bieniasz PD | title = Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu | journal = Nature | volume = 451 | issue = 7177 | pages = 425–430 | date = January 2008 | pmid = 18200009 | doi = 10.1038/nature06553 | doi-access = free | bibcode = 2008Natur.451..425N }}

Tetherin/BST2 and BST1 genes are unregulated by the Nicotinamide (NAM) metabolism pathway.{{cite journal | vauthors = Jung J, Kim LJ, Wang X, Wu Q, Sanvoranart T, Hubert CG, Prager BC, Wallace LC, Jin X, Mack SC, Rich JN | display-authors = 6 | title = Nicotinamide metabolism regulates glioblastoma stem cell maintenance | journal = JCI Insight | volume = 2 | issue = 10 | date = May 2017 | pmid = 28515364 | pmc = 5436539 | doi = 10.1172/jci.insight.90019 }}

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{{cite journal | vauthors = Sakuma T, Noda T, Urata S, Kawaoka Y, Yasuda J | title = Inhibition of Lassa and Marburg virus production by tetherin | journal = Journal of Virology | volume = 83 | issue = 5 | pages = 2382–2385 | date = March 2009 | pmid = 19091864 | pmc = 2643706 | doi = 10.1128/JVI.01607-08 }}{{cite web | url = http://www.aidsmap.com/en/news/34872677-605F-401E-8F73-4F146134BAAE.asp | title = Tetherin: a newly discovered host cell protein that inhibits HIV replication | author = Thaczuk D | date = 2008-02-11 | publisher = NAM AIDS Map }} 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.{{cite journal | vauthors = Royer DJ, Carr DJ | title = A STING-dependent innate-sensing pathway mediates resistance to corneal HSV-1 infection via upregulation of the antiviral effector tetherin | journal = Mucosal Immunology | volume = 9 | issue = 4 | pages = 1065–1075 | date = July 2016 | pmid = 26627457 | pmc = 4889566 | doi = 10.1038/mi.2015.124 }} 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.{{cite journal | vauthors = Olety B, Peters P, Wu Y, Usami Y, Göttlinger H | title = HIV-1 propagation is highly dependent on basal levels of the restriction factor BST2 | journal = Science Advances | volume = 7 | issue = 44 | pages = eabj7398 | date = October 2021 | pmid = 34714669 | pmc = 8555903 | doi = 10.1126/sciadv.abj7398 }}

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.{{cite journal | vauthors = Andrew AJ, Miyagi E, Kao S, Strebel K | title = The formation of cysteine-linked dimers of BST-2/tetherin is important for inhibition of HIV-1 virus release but not for sensitivity to Vpu | journal = Retrovirology | volume = 6 | pages = 80 | date = September 2009 | pmid = 19737401 | pmc = 2754425 | doi = 10.1186/1742-4690-6-80 | doi-access = free }} 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.{{cite journal | vauthors = Evans DT, Serra-Moreno R, Singh RK, Guatelli JC | title = BST-2/tetherin: a new component of the innate immune response to enveloped viruses | journal = Trends in Microbiology | volume = 18 | issue = 9 | pages = 388–396 | date = September 2010 | pmid = 20688520 | pmc = 2956607 | doi = 10.1016/j.tim.2010.06.010 }} 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 Vpu{{cite journal | vauthors = Neil SJ, Zang T, Bieniasz PD | title = Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu | journal = Nature | volume = 451 | issue = 7177 | pages = 425–430 | date = January 2008 | pmid = 18200009 | doi = 10.1038/nature06553 | doi-access = free | bibcode = 2008Natur.451..425N }} which is thought to work by targeting tetherin for degradation via the β-TrCP2 dependent pathway.{{cite journal | vauthors = Mangeat B, Gers-Huber G, Lehmann M, Zufferey M, Luban J, Piguet V | title = HIV-1 Vpu neutralizes the antiviral factor Tetherin/BST-2 by binding it and directing its beta-TrCP2-dependent degradation | journal = PLOS Pathogens | volume = 5 | issue = 9 | pages = e1000574 | date = September 2009 | pmid = 19730691 | pmc = 2729927 | doi = 10.1371/journal.ppat.1000574 | doi-access = free }}{{cite journal | vauthors = Iwabu Y, Fujita H, Kinomoto M, Kaneko K, Ishizaka Y, Tanaka Y, Sata T, Tokunaga K | display-authors = 6 | title = HIV-1 accessory protein Vpu internalizes cell-surface BST-2/tetherin through transmembrane interactions leading to lysosomes | journal = The Journal of Biological Chemistry | volume = 284 | issue = 50 | pages = 35060–35072 | date = December 2009 | pmid = 19837671 | pmc = 2787367 | doi = 10.1074/jbc.M109.058305 | doi-access = free }}

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

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. 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. Vpu interacts with tetherin by interacting with the protein at its transmembrane domain and recruiting β-TrCP2, which causes 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.{{cite journal | vauthors = Laplana M, Caruz A, Pineda JA, Puig T, Fibla J | title = Association of BST-2 gene variants with HIV disease progression underscores the role of BST-2 in HIV type 1 infection | journal = The Journal of Infectious Diseases | volume = 207 | issue = 3 | pages = 411–419 | date = February 2013 | pmid = 23148293 | doi = 10.1093/infdis/jis685 | doi-access = free }} Another primate lentivirus, SIV, also, counteracts tetherin by their removal from the plasma membrane.{{cite journal | vauthors = Jia B, Serra-Moreno R, Neidermyer W, Rahmberg A, Mackey J, Fofana IB, Johnson WE, Westmoreland S, Evans DT | display-authors = 6 | title = Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2 | journal = PLOS Pathogens | volume = 5 | issue = 5 | pages = e1000429 | date = May 2009 | pmid = 19436700 | pmc = 2673686 | doi = 10.1371/journal.ppat.1000429 | doi-access = free }}{{cite journal | vauthors = Harris RS, Hultquist JF, Evans DT | title = The restriction factors of human immunodeficiency virus | journal = The Journal of Biological Chemistry | volume = 287 | issue = 49 | pages = 40875–40883 | date = November 2012 | pmid = 23043100 | pmc = 3510791 | doi = 10.1074/jbc.R112.416925 | doi-access = free }} KSHV protein K5 also targets tetherin for degradation through ubiquitination.{{cite journal | vauthors = Mansouri M, Viswanathan K, Douglas JL, Hines J, Gustin J, Moses AV, Früh K | title = Molecular mechanism of BST2/tetherin downregulation by K5/MIR2 of Kaposi's sarcoma-associated herpesvirus | journal = Journal of Virology | volume = 83 | issue = 19 | pages = 9672–9681 | date = October 2009 | pmid = 19605472 | pmc = 2748026 | doi = 10.1128/JVI.00597-09 }} 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.{{cite journal | vauthors = Bampi C, Rasga L, Roux L | title = Antagonism to human BST-2/tetherin by Sendai virus glycoproteins | journal = The Journal of General Virology | volume = 94 | issue = Pt 6 | pages = 1211–1219 | date = June 2013 | pmid = 23468424 | pmc = 3709622 | doi = 10.1099/vir.0.051771-0 }} CHIKV protein nsP1 interacts with tetherin by disrupting the tetherin-virion complex formation.{{cite journal | vauthors = Jones PH, Maric M, Madison MN, Maury W, Roller RJ, Okeoma CM | title = BST-2/tetherin-mediated restriction of chikungunya (CHIKV) VLP budding is counteracted by CHIKV non-structural protein 1 (nsP1) | journal = Virology | volume = 438 | issue = 1 | pages = 37–49 | date = March 2013 | pmid = 23411007 | pmc = 4086190 | doi = 10.1016/j.virol.2013.01.010 }}

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.

BST2/tetherin is a potent inhibitor of SARS-CoV-2.{{cite journal| author=Martin-Sancho L, Lewinski MK, Pache L, Stoneham CA, Yin X, Pratt D | display-authors=etal| title=Functional Landscape of SARS-CoV-2 Cellular Restriction. | journal=bioRxiv | year= 2020 | volume= | issue= | pages= | pmid=33024967 | doi=10.1101/2020.09.29.319566 | pmc=7536870 }}

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.{{cite journal | vauthors = El-Sherbiny YM, Md Yusof MY, Psarras A, Hensor EM, Kabba KZ, Dutton K, Mohamed AA, Elewaut D, McGonagle D, Tooze R, Doody G, Wittmann M, Emery P, Vital EM | display-authors = 6 | title = B Cell Tetherin: A Flow Cytometric Cell-Specific Assay for Response to Type I Interferon Predicts Clinical Features and Flares in Systemic Lupus Erythematosus | journal = Arthritis & Rheumatology | volume = 72 | issue = 5 | pages = 769–779 | date = May 2020 | pmid = 31804007 | doi = 10.1002/art.41187 | pmc = 8653884 | doi-access = free }} 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.{{cite journal | vauthors = Billcliff PG, Rollason R, Prior I, Owen DM, Gaus K, Banting G | title = CD317/tetherin is an organiser of membrane microdomains | journal = Journal of Cell Science | volume = 126 | issue = Pt 7 | pages = 1553–1564 | date = April 2013 | pmid = 23378022 | pmc = 3647434 | doi = 10.1242/jcs.112953 }} For some viruses, such as Dengue virus, tetherin inhibits the budding of virions as well as cell-to-cell transmission of the virus.{{cite journal | vauthors = Pan XB, Han JC, Cong X, Wei L | title = BST2/tetherin inhibits dengue virus release from human hepatoma cells | journal = PLOS ONE | volume = 7 | issue = 12 | pages = e51033 | year = 2012 | pmid = 23236425 | pmc = 3517589 | doi = 10.1371/journal.pone.0051033 | doi-access = free | bibcode = 2012PLoSO...751033P }} 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.{{cite journal | vauthors = Viswanathan K, Smith MS, Malouli D, Mansouri M, Nelson JA, Früh K | title = BST2/Tetherin enhances entry of human cytomegalovirus | journal = PLOS Pathogens | volume = 7 | issue = 11 | pages = e1002332 | date = November 2011 | pmid = 22072961 | pmc = 3207899 | doi = 10.1371/journal.ppat.1002332 | doi-access = free }}

{{reflist|35em}}

{{refbegin|35em}}

• {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–174 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
• {{cite journal | vauthors = Furuya Y, Takasawa S, Yonekura H, Tanaka T, Takahara J, Okamoto H | title = Cloning of a cDNA encoding rat bone marrow stromal cell antigen 1 (BST-1) from the islets of Langerhans | journal = Gene | volume = 165 | issue = 2 | pages = 329–330 | date = November 1995 | pmid = 8522202 | doi = 10.1016/0378-1119(95)00540-M }}
• {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–156 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
• {{cite journal | vauthors = Ohtomo T, Sugamata Y, Ozaki Y, Ono K, Yoshimura Y, Kawai S, Koishihara Y, Ozaki S, Kosaka M, Hirano T, Tsuchiya M | display-authors = 6 | title = Molecular cloning and characterization of a surface antigen preferentially overexpressed on multiple myeloma cells | journal = Biochemical and Biophysical Research Communications | volume = 258 | issue = 3 | pages = 583–591 | date = May 1999 | pmid = 10329429 | doi = 10.1006/bbrc.1999.0683 }}
• {{cite journal | vauthors = Vidal-Laliena M, Romero X, March S, Requena V, Petriz J, Engel P | title = Characterization of antibodies submitted to the B cell section of the 8th Human Leukocyte Differentiation Antigens Workshop by flow cytometry and immunohistochemistry | journal = Cellular Immunology | volume = 236 | issue = 1–2 | pages = 6–16 | year = 2006 | pmid = 16157322 | doi = 10.1016/j.cellimm.2005.08.002 }}
• {{cite journal | vauthors = Elortza F, Mohammed S, Bunkenborg J, Foster LJ, Nühse TS, Brodbeck U, Peck SC, Jensen ON | display-authors = 6 | title = Modification-specific proteomics of plasma membrane proteins: identification and characterization of glycosylphosphatidylinositol-anchored proteins released upon phospholipase D treatment | journal = Journal of Proteome Research | volume = 5 | issue = 4 | pages = 935–943 | date = April 2006 | pmid = 16602701 | doi = 10.1021/pr050419u }}
• {{cite journal | vauthors = Laplana M, Caruz A, Pineda JA, Puig T, Fibla J | title = Association of BST-2 gene variants with HIV disease progression underscores the role of BST-2 in HIV type 1 infection | journal = The Journal of Infectious Diseases | volume = 207 | issue = 3 | pages = 411–419 | date = February 2013 | pmid = 23148293 | doi = 10.1093/infdis/jis685 | doi-access = free }}

{{refend}}

• {{MeshName|BST2+protein,+human}}

{{NLM content}}

{{Clusters of differentiation}}

Category:HIV/AIDS

Category:Clusters of differentiation