Tetherin, also known as bone marrow stromal antigen 2, is a lipid raft associated
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''BST2''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
In addition, tetherin has been designated as CD317 (
cluster of differentiation
The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...
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.
Gene activation
Tetherin is part of
IFN
Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...
-dependent antiviral response pathway. When the presence of virus and viral components is detected by recognition molecules such as (
RIG-I
RIG-I (retinoic acid-inducible gene I) is a cytosolic pattern recognition receptor (PRR) responsible for the type-1 interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that have been infect ...
), a cascades of interactions happen between signaling molecules, eventually the signal reaches the nucleus to upregulate the expression of
interferon-stimulated gene An interferon-stimulated gene (ISG) is a gene that can be expressed in response to stimulation by interferon. Interferons bind to receptors on the surface of a cell, initiating protein signaling pathways within the cell. This interaction leads to t ...
s (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
Bst1 (Bone marrow stromal cell antigen 1, ADP-ribosyl cyclase 2, CD157) is an enzyme that in humans is encoded by the ''BST1'' gene. CD157 is a paralog of CD38, both of which are located on chromosome 4 (4p15) in humans.
Bst1 is a stromal cell l ...
genes are unregulated by the
Nicotinamide
Niacinamide or Nicotinamide (NAM) is a form of vitamin B3 found in food and used as a dietary supplement and medication. As a supplement, it is used by mouth to prevent and treat pellagra (niacin deficiency). While nicotinic acid (niacin) may ...
(NAM) metabolism pathway.
[ ]
Function
Tetherin is a human cellular protein which inhibits
retrovirus
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...
infection by preventing the diffusion of virus particles after budding from infected cells. Initially discovered as an inhibitor to
HIV-1
The subtypes of HIV include two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to viruses found in the sooty mangabey ...
infection in the absence of
Vpu
VPU may refer to:
Technology
* Video processing unit and visual processing unit, related to graphics processing units
* Vision processing unit, a class of processor intended for accelerating machine vision tasks
* Vector processing unit, a specia ...
, tetherin has also been shown to inhibit the release of other
RNA virus
An RNA virus is a virusother than a retrovirusthat has ribonucleic acid (RNA) as its genetic material. The nucleic acid is usually single-stranded RNA ( ssRNA) but it may be double-stranded (dsRNA). Notable human diseases caused by RNA viruses ...
es such as the
Lassa and
Marburg
Marburg ( or ) is a university town in the German federal state (''Bundesland'') of Hesse, capital of the Marburg-Biedenkopf district (''Landkreis''). The town area spreads along the valley of the river Lahn and has a population of approximate ...
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
A DNA virus is a virus that has a genome made of deoxyribonucleic acid (DNA) that is replicated by a DNA polymerase. They can be divided between those that have two strands of DNA in their genome, called double-stranded DNA (dsDNA) viruses, and ...
HSV-1
Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...
.
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.
Structure
Tetherin is a
type 2 integral membrane protein, with the
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
in the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
, one membrane spanning domain, and a
C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
modified by the addition of a
glycosyl-phosphatidylinositol
Glycosylphosphatidylinositol (), or glycophosphatidylinositol, or GPI in short, is a phosphoglyceride that can be attached to the C-terminus of a protein during posttranslational modification. The resulting GPI-anchored proteins play key roles in ...
(gpi) anchor.
The transmembrane of tetherin is predicted to be a single alpha helix. The ectodomain consists of alpha helical
coiled-coil
A coiled coil is a structural motif in proteins in which 2–7
alpha helix, alpha-helices are coiled together like the strands of a rope. (Protein dimer, Dimers and Protein trimer, trimers are the most common types.) Many coiled coil-type protei ...
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.
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
VPU may refer to:
Technology
* Video processing unit and visual processing unit, related to graphics processing units
* Vision processing unit, a class of processor intended for accelerating machine vision tasks
* Vector processing unit, a specia ...
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
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
within the
coiled coil
A coiled coil is a structural motif in proteins in which 2–7
alpha-helices are coiled together like the strands of a rope. (Dimers and trimers are the most common types.) Many coiled coil-type proteins are involved in important biological fun ...
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
Virus-like particles (VLPs) are molecules that closely resemble viruses, but are non-infectious because they contain no viral genetic material. They can be naturally occurring or synthesized through the individual expression of viral structural pro ...
) 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
VPU may refer to:
Technology
* Video processing unit and visual processing unit, related to graphics processing units
* Vision processing unit, a class of processor intended for accelerating machine vision tasks
* Vector processing unit, a specia ...
interacts with tetherin by interacting with the protein at its transmembrane domain and recruiting
β-TrCP2, which causes
ubiquitination
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
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.
Another primate
lentivirus
''Lentivirus'' is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lent ...
, 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.
Sendai virus proteins HN and F direct tethrin to endosomes or proteasome for degradation.
CHIKV protein nsP1 interacts with tetherin by disrupting the tetherin-virion complex formation.
Cell-to-cell transmission through
virological synapse Viral synapse (or virological synapse) is a molecularly organized cellular junction that is similar in some aspects to immunological synapses. Many viruses including herpes simplex virus (HSV), human immunodeficiency virus (HIV) and human T-lymphot ...
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 Viral synapse (or virological synapse) is a molecularly organized cellular junction that is similar in some aspects to immunological synapses. Many viruses including herpes simplex virus (HSV), human immunodeficiency virus (HIV) and human T-lymphot ...
.
BST2/tetherin is a potent inhibitor of
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
.
[ ]
Tetherin as a biomarker and Other functions
Tetherin has been shown as a Type-I-IFN
biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
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
Dengue fever is a mosquito-borne tropical disease caused by the dengue virus. Symptoms typically begin three to fourteen days after infection. These may include a high fever, headache, vomiting, muscle and joint pains, and a characteristic ...
virus, tetherin inhibits the budding of virions as well as cell-to-cell transmission of the virus.
For human cytomegalovirus (
HCMV
''Human betaherpesvirus 5'', also called human cytomegalovirus (HCMV), is species of virus in the genus ''Cytomegalovirus'', which in turn is a member of the viral family known as ''Herpesviridae'' or herpesviruses. It is also commonly called ...
), tetherin promotes entry of the virus, especially during cell differentiation. It has also been shown that tetherin is incorporated into newly formed virions.
References
Further reading
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External links
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{{Clusters of differentiation
HIV/AIDS
Clusters of differentiation