Tetherin Explained

Tetherin, also known as bone marrow stromal antigen 2, is a lipid raft associated protein that in humans is encoded by the BST2 gene.[1] [2] [3] In addition, tetherin has been designated as CD317 (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.[4] [5]

Gene activation

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.[6] [7] [8]

Tetherin/BST2 and BST1 genes are unregulated by the Nicotinamide (NAM) metabolism pathway.[9]

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[10] [11] 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.[12] 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.[13]

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.[14] 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.[15] 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.[3] 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[16] which is thought to work by targeting tetherin for degradation via the β-TrCP2 dependent pathway.[17] [18]

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[4]

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. Their unique topology allows them to be in the cell through their N-terminus while using the GPI anchor to attach to budding virions.[15] 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.[19] Another primate lentivirus, SIV, also, counteracts tetherin by their removal from the plasma membrane.[20] [21] KSHV protein K5 also targets tetherin for degradation through ubiquitination.[22] 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.[6] Sendai virus proteins HN and F direct tethrin to endosomes or proteasome for degradation.[23] CHIKV protein nsP1 interacts with tetherin by disrupting the tetherin-virion complex formation.[24]

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.[4]

BST2/tetherin is a potent inhibitor of SARS-CoV-2.[25]

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.[26] 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.[27] For some viruses, such as Dengue virus, tetherin inhibits the budding of virions as well as cell-to-cell transmission of the virus.[28] 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.[29]

Further reading

Notes and References

  1. Ishikawa J, Kaisho T, Tomizawa H, Lee BO, Kobune Y, Inazawa J, Oritani K, Itoh M, Ochi T, Ishihara K . 6 . 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 . 3 . 527–534 . April 1995 . 7607676 . 10.1016/0888-7543(95)80171-H .
  2. Web site: Entrez Gene: BST2 bone marrow stromal cell antigen 2.
  3. Rollason R, Korolchuk V, Hamilton C, Schu P, Banting G . Clathrin-mediated endocytosis of a lipid-raft-associated protein is mediated through a dual tyrosine motif . Journal of Cell Science . 120 . Pt 21 . 3850–3858 . November 2007 . 17940069 . 10.1242/jcs.003343 . free .
  4. Le Tortorec A, Willey S, Neil SJ . Antiviral inhibition of enveloped virus release by tetherin/BST-2: action and counteraction . Viruses . 3 . 5 . 520–540 . May 2011 . 21994744 . 3185764 . 10.3390/v3050520 . free .
  5. 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 . 6 . B Cell Tetherin: A Flow Cytometric Cell-Specific Assay for Response to Type I Interferon Predicts Clinical Features and Flares in Systemic Lupus Erythematosus . Arthritis & Rheumatology . 72 . 5 . 769–779 . May 2020 . 31804007 . 10.1002/art.41187 . 8653884 . free .
  6. Kühl A, Pöhlmann S . How Ebola virus counters the interferon system . Zoonoses and Public Health . 59 . Suppl 2 . 116–131 . September 2012 . 22958256 . 7165950 . 10.1111/j.1863-2378.2012.01454.x .
  7. Douglas JL, Gustin JK, Viswanathan K, Mansouri M, Moses AV, Früh K . The great escape: viral strategies to counter BST-2/tetherin . PLOS Pathogens . 6 . 5 . e1000913 . May 2010 . 20485522 . 2869331 . 10.1371/journal.ppat.1000913 . free .
  8. Neil SJ, Zang T, Bieniasz PD . Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu . Nature . 451 . 7177 . 425–430 . January 2008 . 18200009 . 10.1038/nature06553 . free . 2008Natur.451..425N .
  9. Jung J, Kim LJ, Wang X, Wu Q, Sanvoranart T, Hubert CG, Prager BC, Wallace LC, Jin X, Mack SC, Rich JN . 6 . Nicotinamide metabolism regulates glioblastoma stem cell maintenance . JCI Insight . 2 . 10 . May 2017 . 28515364 . 5436539 . 10.1172/jci.insight.90019 .
  10. Sakuma T, Noda T, Urata S, Kawaoka Y, Yasuda J . Inhibition of Lassa and Marburg virus production by tetherin . Journal of Virology . 83 . 5 . 2382–2385 . March 2009 . 19091864 . 2643706 . 10.1128/JVI.01607-08 .
  11. Web site: Tetherin: a newly discovered host cell protein that inhibits HIV replication . Thaczuk D . 2008-02-11 . NAM AIDS Map .
  12. Royer DJ, Carr DJ . A STING-dependent innate-sensing pathway mediates resistance to corneal HSV-1 infection via upregulation of the antiviral effector tetherin . Mucosal Immunology . 9 . 4 . 1065–1075 . July 2016 . 26627457 . 4889566 . 10.1038/mi.2015.124 .
  13. Olety B, Peters P, Wu Y, Usami Y, Göttlinger H . HIV-1 propagation is highly dependent on basal levels of the restriction factor BST2 . Science Advances . 7 . 44 . eabj7398 . October 2021 . 34714669 . 8555903 . 10.1126/sciadv.abj7398 .
  14. Andrew AJ, Miyagi E, Kao S, Strebel K . 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 . Retrovirology . 6 . 80 . September 2009 . 19737401 . 2754425 . 10.1186/1742-4690-6-80 . free .
  15. Evans DT, Serra-Moreno R, Singh RK, Guatelli JC . BST-2/tetherin: a new component of the innate immune response to enveloped viruses . Trends in Microbiology . 18 . 9 . 388–396 . September 2010 . 20688520 . 2956607 . 10.1016/j.tim.2010.06.010 .
  16. Neil SJ, Zang T, Bieniasz PD . Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu . Nature . 451 . 7177 . 425–430 . January 2008 . 18200009 . 10.1038/nature06553 . free . 2008Natur.451..425N .
  17. Mangeat B, Gers-Huber G, Lehmann M, Zufferey M, Luban J, Piguet V . HIV-1 Vpu neutralizes the antiviral factor Tetherin/BST-2 by binding it and directing its beta-TrCP2-dependent degradation . PLOS Pathogens . 5 . 9 . e1000574 . September 2009 . 19730691 . 2729927 . 10.1371/journal.ppat.1000574 . free .
  18. Iwabu Y, Fujita H, Kinomoto M, Kaneko K, Ishizaka Y, Tanaka Y, Sata T, Tokunaga K . 6 . HIV-1 accessory protein Vpu internalizes cell-surface BST-2/tetherin through transmembrane interactions leading to lysosomes . The Journal of Biological Chemistry . 284 . 50 . 35060–35072 . December 2009 . 19837671 . 2787367 . 10.1074/jbc.M109.058305 . free .
  19. Laplana M, Caruz A, Pineda JA, Puig T, Fibla J . Association of BST-2 gene variants with HIV disease progression underscores the role of BST-2 in HIV type 1 infection . The Journal of Infectious Diseases . 207 . 3 . 411–419 . February 2013 . 23148293 . 10.1093/infdis/jis685 . free .
  20. Jia B, Serra-Moreno R, Neidermyer W, Rahmberg A, Mackey J, Fofana IB, Johnson WE, Westmoreland S, Evans DT . 6 . Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2 . PLOS Pathogens . 5 . 5 . e1000429 . May 2009 . 19436700 . 2673686 . 10.1371/journal.ppat.1000429 . free .
  21. Harris RS, Hultquist JF, Evans DT . The restriction factors of human immunodeficiency virus . The Journal of Biological Chemistry . 287 . 49 . 40875–40883 . November 2012 . 23043100 . 3510791 . 10.1074/jbc.R112.416925 . free .
  22. Mansouri M, Viswanathan K, Douglas JL, Hines J, Gustin J, Moses AV, Früh K . Molecular mechanism of BST2/tetherin downregulation by K5/MIR2 of Kaposi's sarcoma-associated herpesvirus . Journal of Virology . 83 . 19 . 9672–9681 . October 2009 . 19605472 . 2748026 . 10.1128/JVI.00597-09 .
  23. Bampi C, Rasga L, Roux L . Antagonism to human BST-2/tetherin by Sendai virus glycoproteins . The Journal of General Virology . 94 . Pt 6 . 1211–1219 . June 2013 . 23468424 . 3709622 . 10.1099/vir.0.051771-0 .
  24. Jones PH, Maric M, Madison MN, Maury W, Roller RJ, Okeoma CM . BST-2/tetherin-mediated restriction of chikungunya (CHIKV) VLP budding is counteracted by CHIKV non-structural protein 1 (nsP1) . Virology . 438 . 1 . 37–49 . March 2013 . 23411007 . 4086190 . 10.1016/j.virol.2013.01.010 .
  25. Martin-Sancho L, Lewinski MK, Pache L, Stoneham CA, Yin X, Pratt D . etal. Functional Landscape of SARS-CoV-2 Cellular Restriction. . bioRxiv . 2020 . 33024967 . 10.1101/2020.09.29.319566 . 7536870 .
  26. 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 . 6 . B Cell Tetherin: A Flow Cytometric Cell-Specific Assay for Response to Type I Interferon Predicts Clinical Features and Flares in Systemic Lupus Erythematosus . Arthritis & Rheumatology . 72 . 5 . 769–779 . May 2020 . 31804007 . 10.1002/art.41187 . 8653884 . free .
  27. Billcliff PG, Rollason R, Prior I, Owen DM, Gaus K, Banting G . CD317/tetherin is an organiser of membrane microdomains . Journal of Cell Science . 126 . Pt 7 . 1553–1564 . April 2013 . 23378022 . 3647434 . 10.1242/jcs.112953 .
  28. Pan XB, Han JC, Cong X, Wei L . BST2/tetherin inhibits dengue virus release from human hepatoma cells . PLOS ONE . 7 . 12 . e51033 . 2012 . 23236425 . 3517589 . 10.1371/journal.pone.0051033 . free . 2012PLoSO...751033P .
  29. Viswanathan K, Smith MS, Malouli D, Mansouri M, Nelson JA, Früh K . BST2/Tetherin enhances entry of human cytomegalovirus . PLOS Pathogens . 7 . 11 . e1002332 . November 2011 . 22072961 . 3207899 . 10.1371/journal.ppat.1002332 . free .

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