Tetherin

• OMIM: 600 534
• UniProt: Q10589

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

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

The induction of the 30-36 kDa Tetherins occurs as part of the antiviral program of a cell by the alpha interferon or - on protein level - during the B- cell activation. Because of its expression in B- lymphocyte protein using the growth of precursor B cells, and the terminal differentiation of plasma cells is associated.

Structure

, Which consists of 180 amino acids tetherin is an integral type 2 transmembrane protein, which is composed of four protein domains: a projecting into the cytoplasm of the amino terminus (N- terminus), a single transmembrane domain, an extracellular domain and a carboxy -terminus (C- terminus) with a glycosyl- phosphatidylinositol anchor (GPI - anchor). Thetherin molecules that have no virus bound are anchored with both ends in the cell membrane. They are represented on the cell surface and in perinuclear compartments of the cell. Here, two tetherin molecules assemble in a parallel orientation to each other creating a stabilized by multiple disulfide homodimer formed.

An antiviral mechanism of action

Tetherin is a human cellular protein, which is induced by IFN alpha and infection with the other retroviruses and enveloped viruses inhibited upon expression on the cell surface by preventing the release of newly formed viruses from infected cells. These "sticks" it - hence the name - the progeny virus to the cell membrane and thus suppresses their budding and the diffusion in the extracellular milieu.

According to current knowledge, the antiviral mechanism of action unfolds as follows: - the transmembrane domain or GPI anchor - When bud off ( budding ) of the virus from the cell surface in the cycle of viral infection, is one of the two membrane domains integrates the Tetherins in the newly formed viral membrane ( viral envelope ), while the other remains in the plasma membrane of the cell. In this way, the newly formed virus remains firmly attached to the cell and can not diffuse away. Seeding ( dissemination) of the viral particles and the associated infection of other cells is thus effectively prevented.

There is much evidence that tetherin is present as a parallel homodimer in the incorporation into the viral envelope. Thus available for the attachment of a virus particle to the cell membrane four anchor available, two each for cell or viral membrane. However, a dimerization of two molecules tetherin does not seem to be essential for the development of anti-viral activity, and it seems to be sufficient if only one of the membrane anchor of the dimer infiltrated the viral envelope.

After studies of the accessory protein Vpu from HIV -1 led to the discovery of tetherin as a novel component of the innate immune defense of the people against retroviruses, could further be shown that tetherin also the release of other enveloped viruses, including the family of filoviruses (eg Marburg virus). , the arenaviruses family (eg, Lassa virus ) and the herpes family of viruses blocked.

Based on the knowledge about the modes of action of tetherin and Vpu, some researchers argue that the inhibition of the function of the viral Vpu protein and the consequent mobilization of the antiviral activity of human Tetherins could constitute a potential strategy in the fight against HIV / AIDS.

Besides tetherin are currently two other antiviral restriction factors known APOBEC3 and TRIM5α. You either lead to inactivating mutations in the Hyper viral genome or to an inactivation of the invading virus capsids and thus differed completely in their mechanism of action from that of the Tetherins.

Blocking of the antiviral activity

In the course of evolution has been able to block some viruses the antiviral effect of Tetherins with the help of certain viral proteins. Examples of such so-called viral antagonists can be found in different strains of enveloped viruses: Vpu protein of HIV -1 Env protein of HIV -2 and SIV Nef protein of SIV, the glycoprotein of the viral envelope ( envelope glycoprotein ) of the Ebola virus, and K5 protein of the human herpesvirus 8 the elimination of Tetherins and other restriction factors contribute not only to increase the pathogenicity of the virus, but also facilitate the transfer from one species to another ( zoonosis ). The underlying antagonistic mechanisms are very diverse and include, as known today, viral co-option ( reinforcing interaction ) endosomal membrane transport processes and a Proteindegradationswege, including ubiquitination is to count. Below are some viral strategies to block tetherin are discussed.

The antiviral activity of tetherin can be prevented by certain accessory proteins of HIV -1 but also HIV-2. Thus, HIV - 1, the main group M ( by major) developed the ability to turn human tetherin extremely efficient means of its Vpu protein without losing the second important function of Vpu, the degradation of the CD4 receptor. By removal of CD4 from the surface of the host cell increases the release of HIV-1 and thus the infectivity or pathogenicity of the virus particles. These special properties of the group M- Vpu protein does not include the members of the other groups (N, O, P) of HIV-1 and HIV-2, is a possible explanation for the high virulence of the particular virus and the pandemic distribution: HI viruses of group M are responsible for almost 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 activity of the antiviral Vpu protein. Thus, the Vpu proteins of strains of HIV -1 O and P no activity against tetherin, while the Vpu of HIV-1 N was able to acquire the anti- tetherin activity, but in return the ability to degradation of the viral receptor CD4 has lost. These strains succeeds therefore much more difficult to master the tetherin barrier, they are not as " optimally " adapted to humans, as the group M viruses, and consequently less common by far.

The exact mechanism of Vpu - controlled Tetherinblockierung is not yet known. However, it is assumed that the viral Vpu, which in turn has a single transmembrane domain that interacts through this with the transmembrane domain of the Tetherins and so this keeps away from the region of virus release. Moreover, the vpu protein presumably causes the introduction of Tetherins in the trans-Golgi network, or in lysosomes, and the subsequent degradation by the β - TrCP2 - dependent pathway.

The second human immunodeficiency virus ( HIV -2) and the Ebola virus pursue another strategy for blocking the Tetherins, by using their envelope proteins for this purpose. While many Affenimmundefizienzviren (SIV) does not have vpu gene have the precursor of HIV-1 ( SIVcpz from chimpanzees and gorillas from SIVgor ) form a VPU without anti- tetherin activity. These viruses use another restriction factor, the multifunctional Nef protein to turn in their respective host organisms that tetherin.

Viral antagonists, as well as the human tetherin, spots, due to their species specificity, a significant hurdle to jump of a virus of some kind (eg chimpanzee ) to another type ( eg, human ) that makes it difficult, in other words it is a zoonosis. In the case of HIV - 1, it is only succeeded the viruses of group M this barrier completely overcome and their triumphant to compete around the world