BST2 - bone marrow stromal cell antigen 2 |Elisa - Clia - Antibody - Protein

Background

Bone Marrow Stromal Cell Antigen 2 (BST2), also known as tetherin, is a type II transmembrane protein that plays a significant role in the immune response. It is involved in antiviral defenses, specifically by restricting the release of enveloped viruses from infected cells. BST2 was first identified on bone marrow stromal cells, but it is now known to be expressed broadly across different cell types, especially in immune cells, including B cells, dendritic cells, and monocytes. Its antiviral function is key for innate immunity, as BST2 restricts viruses like HIV, Ebola, and others by physically tethering budding virions to the cell surface, preventing their release into the extracellular environment where they can infect new cells.

BST2 is also implicated in various physiological processes beyond viral restriction, including immune signaling, cell adhesion, and tumor development. Its expression is upregulated by interferons, a group of cytokines involved in immune signaling, which is indicative of its role in responding to infections and potentially other stressors within the body.

Protein Structure

BST2 is a relatively small protein with unique structural features that are crucial for its function:

Transmembrane Domain:

• BST2 is a type II transmembrane protein, meaning it has a single-pass transmembrane segment located near the N-terminal region. This domain anchors BST2 to the cell membrane, with the N-terminus located in the cytoplasm and the remainder of the protein extending outside the cell.

Extracellular Coiled-Coil Domain:

• The majority of BST2 is located extracellularly and consists of an extended coiled-coil structure. The coiled-coil domain is rich in α-helices, which allows BST2 to form dimers or multimers, a structural arrangement necessary for its antiviral function.
• The coiled-coil region is involved in the formation of parallel homodimers, which are stabilized by disulfide bonds between cysteine residues. This multimeric structure is essential for the tethering function, enabling BST2 to physically link virions to the cell membrane.

GPI Anchor:

• BST2 has a glycosylphosphatidylinositol (GPI) anchor at its C-terminus, which anchors the extracellular portion to the membrane. This GPI anchor is unique to BST2 and enables it to “tether” viral particles by embedding itself in both the plasma membrane of the cell and the lipid envelope of the budding virion, thereby restricting the virus's release.
• The GPI anchor contributes to the protein’s stability within lipid rafts (microdomains within the cell membrane), which is important for the spatial organization of BST2 and its interaction with viral particles.

N-linked Glycosylation Sites:

• BST2 contains two N-linked glycosylation sites within its extracellular domain. These glycosylation modifications enhance protein stability, protect it from proteolytic degradation, and are critical for its antiviral function. The glycosylated regions aid in immune recognition and help prevent viral escape from the immune response.

Classification and Subtypes

BST2 is classified as a type II transmembrane protein and is part of the tetherin family, characterized by its antiviral tethering ability. Unlike many other antiviral proteins, BST2 is unique in its structural composition, enabling it to anchor both to the cell membrane and viral particles. While no isoforms or subtypes have been widely characterized for BST2, there is evidence that post-translational modifications, such as glycosylation and phosphorylation, can modulate its activity and interactions with other proteins.

Function and Biological Significance

BST2 is essential in the host’s innate immune response to viral infections and contributes to immune signaling:

Antiviral Activity:

• The primary function of BST2 is to inhibit the release of enveloped viruses from the host cell. By anchoring viral particles to the cell membrane, BST2 prevents them from detaching, thereby reducing the spread of infection. This antiviral function has been well documented for viruses such as HIV-1, influenza A virus, and Ebola.
• Viruses counteract BST2's effects through various mechanisms, including viral proteins that directly inhibit BST2 function. For instance, the HIV-1 Vpu protein interacts with BST2 to degrade it, allowing the virus to evade BST2-mediated restriction.

Immune Activation and Signaling:

• BST2 plays a role in activating the immune system beyond its antiviral action. It can stimulate NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling, an essential pathway for immune activation. This signaling helps enhance the production of pro-inflammatory cytokines, which promote immune responses.
• BST2 also acts as an interferon-stimulated gene (ISG), meaning its expression is upregulated in response to interferon signaling. This responsiveness to interferons allows BST2 to participate in a feedback loop that enhances immune responses to viral infections.

Role in Cancer:

• BST2 has been associated with various cancer types, including breast and prostate cancers. Its expression is often elevated in tumor cells, and it may play a role in tumor cell adhesion, migration, and immune evasion. BST2 promotes cell survival and resistance to stress-induced apoptosis, which could contribute to cancer progression.
• Elevated levels of BST2 in tumor microenvironments may influence immune responses and contribute to cancer-associated inflammation. Research on BST2’s role in cancer is ongoing, with a focus on understanding how its interaction with immune cells in the tumor environment could be leveraged therapeutically.

Cell Adhesion:

• BST2 contributes to cell adhesion, particularly in immune cells. Its interactions with the extracellular matrix and other cell surface proteins suggest a potential role in immune cell trafficking and localization within tissues. This function may support immune surveillance and the targeting of infected or cancerous cells.

Clinical Issues

BST2’s role in antiviral defense and cancer biology has drawn attention to its clinical relevance:

HIV and Viral Infections:

• BST2 is a critical factor in controlling HIV-1 release from infected cells. However, HIV-1 Vpu protein can target BST2 for degradation, enabling viral escape. Understanding the interaction between BST2 and Vpu has therapeutic implications, as targeting this interaction could restore BST2 function and reduce HIV-1 infectivity.
• Other viruses, such as Ebola and Lassa fever virus, also counteract BST2, suggesting that boosting BST2 function could be a broad-spectrum antiviral strategy. Small molecules or biologics that enhance BST2’s stability or expression might be developed to prevent viral immune evasion.

Cancer:

• Due to its overexpression in some cancers, BST2 has been explored as a potential biomarker. Its role in tumor cell adhesion and immune modulation makes it a candidate for targeting in anti-cancer therapies. Reducing BST2 expression or blocking its function could impair tumor growth and metastasis, making BST2 a therapeutic target.
• BST2’s role in immune signaling could also be leveraged to enhance immune responses against tumors. However, further research is needed to understand its exact mechanisms in different types of cancer.

Autoimmune Diseases:

• Given its immune-regulatory functions, aberrant BST2 expression could be involved in autoimmune conditions. Overactive BST2 signaling could promote inflammation and immune cell activation, potentially contributing to autoimmune pathogenesis. However, research is still in its early stages regarding BST2’s role in autoimmune diseases.

Interferonopathies:

• BST2 is an interferon-stimulated gene, and dysregulated interferon responses can lead to interferonopathies, a group of disorders characterized by chronic inflammation. If BST2 is excessively upregulated, it could exacerbate inflammation in conditions driven by overactive interferon signaling, though specific clinical associations are yet to be fully elucidated.

Summary

BST2, or tetherin, is a multifunctional protein central to antiviral defense, immune signaling, and potentially cancer progression. Its unique structure, featuring a transmembrane domain, extracellular coiled-coil domain, and GPI anchor, enables it to “tether” viral particles to the cell surface, thereby restricting viral release and spread. In addition to its antiviral role, BST2 is involved in immune cell adhesion, NF-κB signaling, and response to interferons, making it a key player in both innate immunity and inflammation.

Clinically, BST2’s antiviral properties have important implications for managing HIV and other viral infections, especially as viruses have evolved mechanisms to inhibit its function. In cancer, BST2 may serve as a biomarker and therapeutic target due to its role in cell adhesion and immune modulation. BST2’s upregulation by interferons highlights its potential involvement in interferonopathies and autoimmune diseases, though further research is needed to fully understand these roles.

Overall, BST2 is a critical immune molecule with diverse functions across antiviral defense, immune regulation, and cellular adhesion, and its clinical relevance spans infectious diseases, oncology, and immunology. Understanding its structural and functional properties could pave the way for novel therapeutic interventions targeting BST2 in various diseases.