Tetherin, also known as bone marrow stromal antigen 2, is a lipid raft associated protein that in humans is encoded by the BST2 gene. [3] [4] [5] 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. [6] [7]
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. [8] [9] [10]
Tetherin/BST2 and BST1 genes are unregulated by the Nicotinamide (NAM) metabolism pathway. [11]
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 [12] [13] 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. [14] 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. [15]
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. [16] 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. [17] 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. [5] 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 [18] which is thought to work by targeting tetherin for degradation via the β-TrCP2 dependent pathway. [19] [20]
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 [6]
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. [6] Their unique topology allows them to be in the cell through their N-terminus while using the GPI anchor to attach to budding virions. [17] 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. [21] Another primate lentivirus, SIV, also, counteracts tetherin by their removal from the plasma membrane. [22] [23] KSHV protein K5 also targets tetherin for degradation through ubiquitination. [24] 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. [8] Sendai virus proteins HN and F direct tethrin to endosomes or proteasome for degradation. [25] CHIKV protein nsP1 interacts with tetherin by disrupting the tetherin-virion complex formation. [26]
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. [6]
BST2/tetherin is a potent inhibitor of SARS-CoV-2. [27]
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. [7] 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. [28] For some viruses, such as Dengue virus, tetherin inhibits the budding of virions as well as cell-to-cell transmission of the virus. [29] 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. [30]
The human immunodeficiency viruses (HIV) are two species of Lentivirus that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype.
Interferons 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 their anti-viral defenses.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is Human gammaherpesvirus 8, or HHV-8 in short. Like other herpesviruses, its informal names are used interchangeably with its formal ICTV name. This virus causes Kaposi's sarcoma, a cancer commonly occurring in AIDS patients, as well as primary effusion lymphoma, HHV-8-associated multicentric Castleman's disease and KSHV inflammatory cytokine syndrome. It is one of seven currently known human cancer viruses, or oncoviruses. Even after many years since the discovery of KSHV/HHV8, there is no known cure for KSHV associated tumorigenesis.
The genome and proteins of HIV (human immunodeficiency virus) have been the subject of extensive research since the discovery of the virus in 1983. "In the search for the causative agent, it was initially believed that the virus was a form of the Human T-cell leukemia virus (HTLV), which was known at the time to affect the human immune system and cause certain leukemias. However, researchers at the Pasteur Institute in Paris isolated a previously unknown and genetically distinct retrovirus in patients with AIDS which was later named HIV." Each virion comprises a viral envelope and associated matrix enclosing a capsid, which itself encloses two copies of the single-stranded RNA genome and several enzymes. The discovery of the virus itself occurred two years following the report of the first major cases of AIDS-associated illnesses.
Herpesviridae is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word ἕρπειν, referring to spreading cutaneous lesions, usually involving blisters, seen in flares of herpes simplex 1, herpes simplex 2 and herpes zoster (shingles). In 1971, the International Committee on the Taxonomy of Viruses (ICTV) established Herpesvirus as a genus with 23 viruses among four groups. As of 2020, 115 species are recognized, all but one of which are in one of the three subfamilies. Herpesviruses can cause both latent and lytic infections.
A viral envelope is the outermost layer of many types of viruses. It protects the genetic material in their life cycle when traveling between host cells. Not all viruses have envelopes. A viral envelope protein or E protein is a protein in the envelope, which may be acquired by the capsid from an infected host cell.
APOBEC3G is a human enzyme encoded by the APOBEC3G gene that belongs to the APOBEC superfamily of proteins. This family of proteins has been suggested to play an important role in innate anti-viral immunity. APOBEC3G belongs to the family of cytidine deaminases that catalyze the deamination of cytidine to uridine in the single stranded DNA substrate. The C-terminal domain of A3G renders catalytic activity, several NMR and crystal structures explain the substrate specificity and catalytic activity.
Molluscum contagiosum virus (MCV) is a species of DNA poxvirus that causes the human skin infection molluscum contagiosum. Molluscum contagiosum affects about 200,000 people a year, about 1% of all diagnosed skin diseases. Diagnosis is based on the size and shape of the skin lesions and can be confirmed with a biopsy, as the virus cannot be routinely cultured. Molluscum contagiosum virus is the only species in the genus Molluscipoxvirus. MCV is a member of the subfamily Chordopoxvirinae of family Poxviridae. Other commonly known viruses that reside in the subfamily Chordopoxvirinae are variola virus and monkeypox virus.
Murine respirovirus, formerly Sendai virus (SeV) and previously also known as murine parainfluenza virus type 1 or hemagglutinating virus of Japan (HVJ), is an enveloped, 150-200 nm–diameter, negative sense, single-stranded RNA virus of the family Paramyxoviridae. It typically infects rodents and it is not pathogenic for humans or domestic animals
Mitochondrial antiviral-signaling protein (MAVS) is a protein that is essential for antiviral innate immunity. MAVS is located in the outer membrane of the mitochondria, peroxisomes, and mitochondrial-associated endoplasmic reticulum membrane (MAM). Upon viral infection, a group of cytosolic proteins will detect the presence of the virus and bind to MAVS, thereby activating MAVS. The activation of MAVS leads the virally infected cell to secrete cytokines. This induces an immune response which kills the host's virally infected cells, resulting in clearance of the virus.
Vpu is an accessory protein that in HIV is encoded by the vpu gene. Vpu stands for "Viral Protein U". The Vpu protein acts in the degradation of CD4 in the endoplasmic reticulum and in the enhancement of virion release from the plasma membrane of infected cells. Vpu induces the degradation of the CD4 viral receptor and therefore participates in the general downregulation of CD4 expression during the course of HIV infection. Vpu-mediated CD4 degradation is thought to prevent CD4-Env binding in the endoplasmic reticulum to facilitate proper Env assembly into virions. It is found in the membranes of infected cells, but not the virus particles themselves.
Rev is a transactivating protein that is essential to the regulation of HIV-1 protein expression. A nuclear localization signal is encoded in the rev gene, which allows the Rev protein to be localized to the nucleus, where it is involved in the export of unspliced and incompletely spliced mRNAs. In the absence of Rev, mRNAs of the HIV-1 late (structural) genes are retained in the nucleus, preventing their translation.
Vpr is a Human immunodeficiency virus gene and protein product. Vpr stands for "Viral Protein R". Vpr, a 96 amino acid 14-kDa protein, plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for virus replication and enhanced gene expression from provirus in dividing or non-dividing cells such as T cells or macrophages. Vpr also induces G2 cell cycle arrest and apoptosis in proliferating cells, which can result in immune dysfunction.
Vpx is a virion-associated protein encoded by human immunodeficiency virus type 2 HIV-2 and most simian immunodeficiency virus (SIV) strains, but that is absent from HIV-1. It is similar in structure to the protein Vpr that is carried by SIV and HIV-2 as well as HIV-1. Vpx is one of five accessory proteins carried by lentiviruses that enhances viral replication by inhibiting host antiviral factors.
Éric A. Cohen is a Canadian molecular virologist whose research is focused on human immunodeficiency virus (HIV)-host interactions that govern viral replication and persistence.
In parasitology and epidemiology, a host switch is an evolutionary change of the host specificity of a parasite or pathogen. For example, the human immunodeficiency virus used to infect and circulate in non-human primates in West-central Africa, but switched to humans in the early 20th century.
Viroporins are small and usually hydrophobic multifunctional viral proteins that modify cellular membranes, thereby facilitating virus release from infected cells. Viroporins are capable of assembling into oligomeric ion channels or pores in the host cell's membrane, rendering it more permeable and thus facilitating the exit of virions from the cell. Many viroporins also have additional effects on cellular metabolism and homeostasis mediated by protein-protein interactions with host cell proteins. Viroporins are not necessarily essential for viral replication, but do enhance growth rates. They are found in a variety of viral genomes but are particularly common in RNA viruses. Many viruses that cause human disease express viroporins. These viruses include hepatitis C virus, HIV-1, influenza A virus, poliovirus, respiratory syncytial virus, and SARS-CoV.
Paul Darren Bieniasz is a British-American virologist whose main area of research is HIV/AIDS. He is currently a professor of retrovirology at the Rockefeller University. He received the 2015 KT Jeang Retrovirology Prize and the 2010 Eli Lilly and Company Research Award. Bieniasz has been a Howard Hughes Medical Institute investigator since 2008.
Serine incorporator 5 is a protein that in humans is encoded by the SERINC5 gene.
The membrane (M) protein is an integral membrane protein that is the most abundant of the four major structural proteins found in coronaviruses. The M protein organizes the assembly of coronavirus virions through protein-protein interactions with other M protein molecules as well as with the other three structural proteins, the envelope (E), spike (S), and nucleocapsid (N) proteins.
{{cite journal}}: CS1 maint: multiple names: authors list (link)This article incorporates text from the United States National Library of Medicine, which is in the public domain.