TNFRSF17 - TNF receptor superfamily member 17 | Elisa - Clia - Antibody - Protein

Background

TNFRSF17, also known as B-cell maturation antigen (BCMA), is a receptor within the tumor necrosis factor receptor superfamily (TNFRSF). It is primarily expressed on B cells, specifically on mature and plasma B cells, where it plays a pivotal role in B cell survival, differentiation, and immunoglobulin secretion. TNFRSF17 is unique among TNFRSF members because of its specificity for binding ligands like APRIL (A Proliferation-Inducing Ligand) and BAFF (B-cell Activating Factor), which are members of the TNF ligand superfamily. BCMA is essential for maintaining long-lived plasma cells and for regulating immune responses, particularly in the context of adaptive immunity.

TNFRSF17 has gained significant attention in immunology and oncology due to its role in supporting the survival and activity of plasma cells. Dysregulated BCMA signaling is implicated in multiple myeloma and other B-cell malignancies, where it promotes abnormal growth and survival of malignant plasma cells. Due to its restricted expression on B cells and malignant plasma cells, TNFRSF17 has become a promising therapeutic target, particularly in multiple myeloma, where BCMA-targeted therapies (such as CAR-T cells and antibody-drug conjugates) are under active development.

Protein Structure

The protein structure of TNFRSF17 is crucial for its interaction with ligands like APRIL and BAFF, which drive its signaling functions in B cells. TNFRSF17 is a transmembrane glycoprotein with a specific structural arrangement that facilitates ligand binding and signal transduction.

Extracellular Domain (ECD):

• The extracellular region of TNFRSF17 contains cysteine-rich domains (CRDs), characteristic of TNFRSF members. These CRDs enable TNFRSF17 to selectively bind APRIL and BAFF, triggering downstream signaling in response to these ligands.
• TNFRSF17 is distinct from other TNFRSF receptors in having only a single CRD. This structural specificity allows it to recognize APRIL and BAFF with high affinity and activate signaling pathways specific to B-cell survival and differentiation.
• The single CRD structure is involved in high-affinity binding to APRIL, with weaker binding to BAFF, allowing TNFRSF17 to specifically regulate the effects of APRIL while being less responsive to BAFF.

Transmembrane Domain (TMD):

• TNFRSF17 has a single-pass transmembrane domain, anchoring it within the cell membrane of B cells. This domain stabilizes the receptor and connects the extracellular ligand-binding domain to the intracellular signaling domain.
• The TMD facilitates conformational changes necessary for activating intracellular signaling pathways upon ligand binding.

Intracellular Domain (ICD):

• The intracellular region of TNFRSF17 is essential for recruiting adaptor proteins necessary for downstream signaling. Upon ligand engagement, the ICD activates various signaling pathways, most notably the NF-κB pathway, essential for B-cell survival and differentiation.
• This domain interacts with TNF receptor-associated factors (TRAFs), such as TRAF1, TRAF2, and TRAF3, which serve as adaptor proteins. These interactions lead to the activation of survival pathways and inhibition of apoptotic signals, ensuring plasma cell longevity.
• TNFRSF17 is unique in its signaling mechanism, primarily activating pathways that enhance plasma cell survival rather than promoting apoptosis, as seen in other TNFRSF receptors.

The structural simplicity and ligand-binding specificity of TNFRSF17 enable it to selectively interact with APRIL and, to a lesser extent, BAFF, triggering pathways that are crucial for B-cell maturation and survival.

Classification and Subtypes

TNFRSF17 belongs to the TNF receptor superfamily (TNFRSF), a group of receptors involved in immune regulation, apoptosis, and cell survival. Within the TNFRSF, TNFRSF17 is closely related to TNFRSF13B (TACI) and TNFRSF13C (BAFF-R), both of which can bind BAFF and APRIL. However, unlike TACI and BAFF-R, TNFRSF17 has high specificity for APRIL and plays a distinct role in plasma cell survival and long-term immune memory.

TNFRSF17 does not have distinct subtypes, but its interactions and signaling can vary based on ligand availability and the presence of co-receptors. For example, TACI and BAFF-R modulate responses to BAFF and APRIL, and the balance of these receptor-ligand interactions determines B cell differentiation, survival, or apoptosis outcomes.

Function and Biological Significance

The biological functions of TNFRSF17 are centered around B cell maturation, plasma cell survival, and immune regulation. The primary functions of TNFRSF17 include:

Plasma Cell Survival:

• TNFRSF17 plays a critical role in supporting the survival of long-lived plasma cells in the bone marrow. This is essential for maintaining long-term immunity, as plasma cells are responsible for producing antibodies following antigen exposure.
• By activating the NF-κB pathway through TRAF adaptor proteins, TNFRSF17 promotes the expression of anti-apoptotic genes, ensuring plasma cell longevity and sustained antibody production.

Immune Regulation and Antibody Production:

• Through its interactions with APRIL and BAFF, TNFRSF17 regulates antibody production by promoting the survival of plasma cells. This helps maintain a pool of antibody-producing cells ready to respond to re-infection or persistent antigens.
• The signaling pathways initiated by TNFRSF17 also help in the differentiation of B cells into antibody-secreting plasma cells, especially after antigen exposure or immunization.

Selective Ligand Binding and Immune Balance:

• TNFRSF17’s high affinity for APRIL allows it to respond to specific immune signals, promoting B-cell differentiation and plasma cell maintenance without overstimulating other B-cell functions. This specificity helps balance immune responses, ensuring antibody production without excessive B-cell proliferation, which could lead to disorders.

Clinical Issues

Multiple Myeloma and B-cell Malignancies:

• TNFRSF17 is highly expressed on multiple myeloma cells, a malignancy of plasma cells. Overexpression of TNFRSF17 in multiple myeloma supports malignant cell survival by enhancing APRIL-mediated signaling, which activates NF-κB and anti-apoptotic pathways in these cells.
• Due to its restricted expression on plasma cells, TNFRSF17 is a valuable therapeutic target in multiple myeloma. BCMA-targeted therapies, such as CAR-T cell therapies and antibody-drug conjugates, are designed to specifically target myeloma cells expressing TNFRSF17, showing promising results in clinical trials.

Autoimmune Diseases:

• Dysregulation of TNFRSF17 signaling can contribute to autoimmune diseases. Excessive APRIL or BAFF signaling through TNFRSF17 can lead to abnormal plasma cell survival and increased antibody production, potentially resulting in the development of autoantibodies and autoimmune pathology.
• Conditions like Systemic Lupus Erythematosus (SLE) may be associated with elevated levels of APRIL and BAFF, which promote B cell survival and autoreactivity through TNFRSF17 and related receptors.

Therapeutic Interventions:

• Therapeutic strategies targeting TNFRSF17 include monoclonal antibodies, antibody-drug conjugates, and CAR-T cell therapies aimed at reducing plasma cell survival in B-cell malignancies. In multiple myeloma, anti-BCMA therapies selectively target TNFRSF17-expressing cells, minimizing effects on other cell types.
• Additionally, research is ongoing into targeting APRIL and BAFF levels to modulate TNFRSF17 activity in autoimmune diseases, aiming to reduce abnormal B cell activity and autoantibody production.

Summary

TNFRSF17, or BCMA, is a crucial receptor in the TNF receptor superfamily, predominantly expressed on mature B cells and plasma cells. Structurally, TNFRSF17 contains a single cysteine-rich domain for APRIL binding, a transmembrane region for cell membrane anchoring, and an intracellular domain that activates signaling pathways critical for cell survival and differentiation. TNFRSF17’s primary ligands, APRIL and BAFF, initiate signaling pathways, particularly NF-κB, that support plasma cell survival, essential for long-term immune memory.

Functionally, TNFRSF17 maintains plasma cell populations in the bone marrow, supporting antibody production and immune responses to recurrent infections. Dysregulated TNFRSF17 signaling is linked to autoimmune diseases and B-cell malignancies, particularly multiple myeloma, where high levels of APRIL/BAFF-mediated signaling support malignant plasma cell survival. TNFRSF17-targeted therapies, such as CAR-T cells and monoclonal antibodies, have shown promise in treating multiple myeloma by selectively targeting this receptor on malignant cells. In autoimmune conditions, therapeutic modulation of BAFF and APRIL levels may help manage disease by reducing B cell survival and autoantibody production. Overall, TNFRSF17 plays an essential role in immune regulation, with its selective expression on plasma cells making it a significant target in both oncology and immunology.