Tetherin

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Tetherin
Tetherin
Tetherin according to 2X7A .

Existing structural data : 2LK9 , 2X7A , 2XG7 , 3MQ7 , 3MQ9 , 3MQB , 3MQC , 3NWH , 4P6Z

Properties of human protein
Mass / length primary structure 19.8 kilodaltons / 180 amino acids (isoform 1)

18.4 kilodaltons / 168 amino acids (isoform 2)

Secondary to quaternary structure Transmembrane protein (Type II), monomer / homodimer
Isoforms 2
Identifier
Gene names BST2 CD317
External IDs
Enzyme classification
Response type Inhibition
Substrate enveloped viruses
Products Cell tetherin virus complex
Orthologue
human House mouse
Entrez 684 69550
Ensemble ENSG00000130303 ENSMUSG00000046718
UniProt Q10589 Q8R2Q8
Refseq (mRNA) NM_004335 NM_198095
Refseq (protein) NP_004326 NP_932763
Gene locus Chr 19: 17.4 - 17.41 Mb Chr 8: 71.53 - 71.54 Mb
PubMed search 684 69550

Tetherin (from English: to tether = to attach), also known as bone marrow stromal antigen 2 , BST2 or HM1.24, is an interferon- induced protein encoded by the BST2 gene in humans . It is a representative of the so-called cluster of differentiation and is listed in the list of human CD antigens as CD317 (cluster of differentiation 317).

Tetherin plays an important role in protecting human cells from infection by viruses by preventing the release of virions (virus particles) from retroviruses and other enveloped viruses. Together with the APOBEC3 protein family and the restriction factor TRIM5α , tetherin is an important component of innate antiviral immunity .

The induction of the 30-36  kDa heavy tetherin occurs as part of a cell's antiviral program by the alpha interferon or - at the protein level - during B-cell activation. Because of its expression in B lymphocytes, the protein has been associated with the growth of precursor B cells and the terminal differentiation of plasma cells .

structure

Consisting of 180 amino acids , tetherin is an integral type 2 transmembrane protein made up of four protein domains : an amino terminus protruding into the cytoplasm (N terminus), a single transmembrane domain , an extracellular domain and a carboxy terminus (C- Terminus) with a glycosyl-phosphatidyl-inositol anchor ( GPI anchor ). Thetherin molecules that have not bound a virus are firmly anchored in the cell membrane with both ends . They are represented on the cell surface and in perinuclear cell compartments . Here, two tetherin molecules are attached to each other in a parallel orientation, creating a homodimer stabilized by several disulfide bridges .

Antiviral mechanism of action

Tetherin is a human cellular protein which is induced by alpha interferon and, after expression on the cell surface, inhibits infection with retroviruses and other enveloped viruses by preventing the release of newly formed viruses from infected cells. Here it "sticks" - hence the name - the virus offspring to the cell membrane and thus suppresses their budding and diffusion into the extracellular environment.

According to the current state of knowledge, the antiviral mechanism of action unfolds as follows: When the virus is budding from the cell surface in the cycle of the virus infection , one of the two membrane domains - the transmembrane domain or the GPI anchor - of the tetherin is integrated into the newly created viral membrane ( Virus envelope ), while the other remains in the cell's plasma membrane . In this way the newly formed virus remains firmly attached to the cell and cannot diffuse away . The sowing ( dissemination ) of the virus particles and the associated infection of other cells is thus effectively prevented.

There is much to suggest that the tetherin is present as a parallel homodimer when it is incorporated into the virus envelope. A total of four membrane anchors are available for attaching a virus particle to the cell, two each for the cell and virus membrane. For the development of the antiviral activity, however, dimerization of two tetherin molecules does not seem to be absolutely necessary, and it also seems sufficient if only one of the two membrane anchors of the dimer infiltrates the virus envelope.

After investigations of the accessory protein Vpu of HIV-1 led to the discovery of tetherin as a novel component of the innate immune defense of humans against retroviruses, it could furthermore be shown that tetherin also releases other enveloped viruses, among others from the family of filoviruses (e.g. . Marburg virus ), the family of the arenaviruses (e.g. Lassa virus ) and the family of the herpes viruses .

Based on the knowledge of the modes of action of tetherin and Vpu, some researchers argue that inhibiting the function of the viral Vpu protein and consequently mobilizing the antiviral activity of human tetherin could represent a potential strategy in the fight against HIV / AIDS.

In addition to tetherin, two other antiviral restriction factors are currently known, APOBEC3 and TRIM5α . They either lead to inactivating hypermutations in the viral genome or to inactivation of the invading virus capsids and thus differ completely in their mechanism of action from that of tetherin.

Blocking antiviral activity

Some viruses block the antiviral effects of tetherin with the help of certain viral proteins. Examples of such so-called viral tetherin antagonists are found in various strains of enveloped viruses: Vpu protein from HIV-1, Env protein from HIV-2 and SIV , Nef protein from SIV, the glycoprotein of the virus envelope ( envelope glycoprotein ) of the Ebola virus , the K5 protein of human herpes virus 8 and the hemagglutinin and neuraminidase of some influenza viruses . The elimination of tetherin and other restriction factors not only contributes to increasing the pathogenicity of the viruses, but also facilitates the transmission from one species to another ( zoonosis ). The underlying antagonistic mechanisms are very different and include, as far as is known today, viral co-option (reinforcing interaction) endosomal membrane transport processes and protein degradation pathways , which also include ubiquitination . Some viral strategies for blocking tetherin are discussed below.

The antiviral activity of tetherin can be suppressed by certain accessory proteins of HIV-1 and HIV-2. HIV-1 of the main group M (from major ) has the ability to switch off human tetherin extremely efficiently by means of its Vpu protein, without losing the second important function of Vpu, the breakdown of the CD4 receptor. The removal of CD4 from the surface of the host cell increases the release and thus the infectivity or pathogenicity of the virus particles. This special property of the group M-Vpu protein, which the members of the other groups (N, O, P) of HIV-1 and HIV-2 do not have, is a possible explanation for the particularly high virulence of these viruses and for Its pandemic spread: Group M HIV viruses are responsible for around 90% of all HIV infections and AIDS cases worldwide. The members of the other groups (N, O, P), on the other hand, do not have the full antiviral activity of the Vpu protein. Thus, the Vpu proteins of strains O and P have no activity against tetherin, while the Vpu of strain N has anti-tetherin activity, but on the other hand does not have the ability to degrade the viral CD4 receptor. It is therefore much more difficult for these strains to master the tetherin barrier; they are not as "optimally" adapted to humans as the group M viruses and consequently by far less common.

The exact mechanism of Vpu-controlled tetherin blocking is not yet known. It is assumed, however, that the viral Vpu, which in turn has a single transmembrane domain, interacts with the transmembrane domain of the tetherin via this and thus keeps it away from the region of the virus release. In addition, the Vpu protein presumably brings about the smuggling of the tetherin into the trans -Golgi network or into lysosomes and the subsequent degradation via the β-TrCP2-dependent path.

The second human immunodeficiency virus (HIV-2) and the Ebola virus use their coat proteins to block the tetherin. While many simian immunodeficiency viruses ( SIV ) do not have a vpu gene, the precursors of HIV-1 (SIVcpz from chimpanzees and SIVgor from gorillas ) form a vpu without anti-tetherin activity. These viruses use another restriction factor, the multifunctional Nef protein, to switch off the tetherin in their respective host organisms.

Viral antagonists, including human tetherin, represent a significant hurdle for a virus to jump from one species (e.g. chimpanzee) to another (e.g. human) due to their species-specificity and thus make zoonosis more difficult . In the case of HIV-1, only Group M viruses have so far been able to completely overcome this barrier.

Web links

Individual evidence

  1. ↑ a b Ishikawa, J. et al .: Molecular cloning and chromosomal mapping of a bone marrow stromal cell surface gene, BST2, that may be involved in pre-B-cell growth . In: Genomics . 26, No. 3, August 1995, pp. 527-534. PMID 7607676 .
  2. ↑ Entrez Gene: BST2 bone marrow stromal cell antigen 2 . Retrieved February 23, 2011.
  3. ↑ a b Vidal-Laliena, M. et al .: Characterization of antibodies submitted to the B cell section of the 8th Human Leukocyte Differentiation Antigens Workshop by flow cytometry and immunohistochemistry . In: Cell Immunol . 236, No. 1-2, August 2005, pp. 6-16. PMID 16157322 .
  4. ↑ a b c Tokarev, A. et al .: Antiviral activity of the interferon-induced cellular protein BST-2 / tetherin . In: AIDS Res Hum Retroviruses . 25, No. 12, December 2009, pp. 1197-1210. PMID 19929170 .
  5. ↑ a b Kupzig, S. et al .: Bst-2 / HM1.24 is a raft-associated apical membrane protein with an unusual topology . In: Traffic . 4, No. 10, 2003, pp. 694-709. PMID 12956872 .
  6. ↑ Ohtomo, T. et al .: Molecular cloning and characterization of a surface antigen preferentially overexpressed on multiple myeloma cells . In: Biochem Biophys Res Commun . 258, No. 3, 1999, pp. 583-591. PMID 10329429 .
  7. ↑ a b c Neil SJ et al .: Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu . In: Nature . 451, No. 7177, January 2008, pp. 425-30. doi : 10.1038 / nature06553 . PMID 18200009 .
  8. ↑ Van Damme, N. et al .: The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein . In: Cell Host Microbe . 3, No. 4, April 2008, pp. 245-252. PMID 18342597 .
  9. ↑ a b Göttlinger, HG: HIV / AIDS: Virus kept on a leash . In: Nature . 451, No. 7177, 2008, pp. 406-408. doi : 10.1038 / nature06364 . PMID 18200012 .
  10. ↑ a b c d Perez-Caballero, D. et al .: Tetherin inhibits HIV-1 release by directly tethering virions to cells . In: Cell . 139, No. 3, 2009, pp. 456-457. PMID 19879838 .
  11. ^ Heinrich G. Göttlinger: Model for tetherin-mediated HIV-1 retention. Figure 1 from the article "HIV / AIDS: Virus kept on a leash". In: Edition 451. Nature , January 24, 2008, pp. 406-408 , accessed on December 26, 2010 (English, A schematic representation of how tetherin-mediated virus retention could take place).
  12. ↑ Andrew, AJ et al .: 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 . In: Retrovirology . 6, 2009, p. 80. doi : 10.1186 / 1742-4690-6-80 . PMID 19737401 . PMC 2754425 (free full text).
  13. ↑ Sakuma, T. et al .: Dimerization of tetherin is not essential for its antiviral activity against Lassa and Marburg viruses . In: PLOS ONE . 4, No. 9, 2009, p. E6934. PMID 19742323 .
  14. ↑ Jouvenet, N. et al .: Broad-spectrum inhibition of retroviral and filoviral particle release by tetherin . In: J. Virol. . 83, No. 4, 2009, pp. 1837-1842. PMID 19036818 .
  15. ↑ Sakuma, T. et al .: Inhibition of Lassa and Marburg virus production by tetherin . In: J. Virol. . 83, No. 5, March 2009, pp. 2382-5. doi : 10.1128 / JVI.01607-08 . PMID 19091864 . PMC 2643706 (free full text).
  16. ↑ Thaczuk D: Tetherin: a newly discovered host cell protein that inhibits HIV replication . NAM AIDS Map. February 11, 2008. Retrieved February 23, 2011.
  17. ↑ a b c d e Kirchhoff, F .: “Optimal” adaptation of pandemic HIV-1 strains to humans . In: BIOspectrum . 2, 2010, pp. 144-148.
  18. ↑ K. Gnirß, P. Zmora, P. Blazejewska, M. Winkler, A. Lins, I. Nehlmeier, S. Gärtner, AS Moldenhauer, H. Hofmann-Winkler, T. Wolff, M. Schindler, S. Pöhlmann: Tetherin Sensitivity of Influenza A Viruses Is Strain Specific: Role of Hemagglutinin and Neuraminidase. In: Journal of virology. Volume 89, number 18, September 2015, pp. 9178-9188, doi : 10.1128 / JVI.00615-15 , PMID 26109730 , PMC 4542344 (free full text).
  19. ↑ Sauter, D. et al .: Tetherin-driven adaptation of Vpu and Nef function and the evolution of pandemic and nonpandemic HIV-1 strains . In: Cell Host Microbe . 6, No. 5, 2009, pp. 409-421. PMID 19917496 .
  20. ↑ a b Ruiz, A. et al .: The Vpu protein: new concepts in virus release and CD4 down-modulation . In: Curr HIV Res . 8, No. 3, April 2010, pp. 240-252. PMID 20201792 .
  21. ↑ Mangeat, B. et al .: HIV-1 Vpu neutralizes the antiviral factor Tetherin / BST-2 by binding it and directing its beta-TrCP2-dependent degradation . In: PLoS Pathog . . 5, No. 9, September 2009, p. E1000574. doi : 10.1371 / journal.ppat.1000574 . PMID 19730691 . PMC 2729927 (free full text).
  22. ↑ Iwabu, Y et al .: HIV-1 accessory protein Vpu internalizes cell-surface BST-2 / tetherin through transmembrane interactions leading to lysosomes. . In: J. Biol. Chem. . 284, No. 50, December 2009, pp. 35060-72. doi : 10.1074 / jbc.M109.058305 . PMID 19837671 .
  23. ↑ Zhang, F. et al .: Nef proteins from simian immunodeficiency viruses are tetherin antagonists . In: Cell Host Microbe . 6, No. 1, 2009, pp. 54-67. PMID 19501037 .