TNFRSF13C - TNF receptor superfamily member 13C | Elisa - Clia - Antibody - Protein

Background

TNFRSF13C, also known as the B-cell activating factor receptor (BAFF-R), is a critical receptor involved in the regulation of B cell survival and maturation within the immune system. It belongs to the tumor necrosis factor receptor superfamily (TNFRSF), with BAFF-R specifically binding BAFF (B-cell activating factor), also known as TNFSF13B. BAFF-R signaling is essential for the differentiation of B cells and their progression through developmental stages, playing a crucial role in both innate and adaptive immunity.

Dysfunction in TNFRSF13C signaling has been implicated in immune-related disorders, including autoimmune diseases and immunodeficiencies. Genetic mutations or dysregulation in BAFF-R and BAFF signaling pathways are associated with conditions such as Systemic Lupus Erythematosus (SLE) and Common Variable Immunodeficiency (CVID), as they can lead to abnormal B cell activity, autoreactivity, and altered antibody production. This receptor is also studied as a therapeutic target for autoimmune diseases, with strategies aimed at modulating BAFF levels to control B cell activity.

Protein Structure

The structure of TNFRSF13C is specialized for ligand binding and initiation of downstream signaling pathways essential for B cell biology. TNFRSF13C, a transmembrane protein, has specific structural domains enabling it to interact with BAFF and trigger intracellular signals upon ligand binding.

Extracellular Domain (ECD):

• The extracellular domain of TNFRSF13C consists of a single cysteine-rich domain (CRD), which distinguishes BAFF-R from other receptors in the TNFRSF. This CRD structure is involved in recognizing and binding BAFF.
• Upon binding to BAFF, the ECD undergoes conformational changes that facilitate signal transduction through the receptor’s intracellular domains. BAFF binding to TNFRSF13C is essential for its activation and subsequent intracellular signaling cascades.

Transmembrane Domain (TMD):

• TNFRSF13C has a single transmembrane domain, anchoring it within the plasma membrane of B cells. This domain supports receptor stability, facilitating interaction between the extracellular BAFF ligand and the receptor’s intracellular domain.

Intracellular Domain (ICD):

• The intracellular domain of TNFRSF13C interacts with downstream signaling proteins, notably TNF receptor-associated factors (TRAFs), particularly TRAF3, which serves as a critical adaptor in the BAFF-R signaling pathway.
• Unlike other TNFRSF members with death domains, TNFRSF13C promotes cell survival rather than apoptosis. Its ICD interacts with TRAF proteins to activate pathways that regulate B cell survival, growth, and differentiation.
• The key pathways downstream of BAFF-R signaling include NF-κB2, which plays a vital role in B cell maturation, survival, and immune response regulation. Upon BAFF binding, NF-κB2 is activated, leading to transcription of genes involved in cell survival and differentiation.

The simplicity of TNFRSF13C’s structure, particularly the presence of only one cysteine-rich domain in its ECD, allows it to specifically recognize BAFF with high affinity, ensuring precise regulation of B cell survival.

Classification and Subtypes

TNFRSF13C belongs to the tumor necrosis factor receptor superfamily (TNFRSF), a family of receptors involved in apoptosis, cell proliferation, and immune response regulation. Within this superfamily, TNFRSF13C is closely related to TNFRSF13B (TACI) and TNFRSF17 (BCMA). Both TACI and BCMA can also bind BAFF, but their functions overlap with and differ from BAFF-R. While TACI and BCMA are involved in both BAFF and APRIL signaling, BAFF-R exclusively binds BAFF and is the primary receptor for BAFF-mediated B cell survival.

There are no distinct structural subtypes of TNFRSF13C; however, genetic polymorphisms and mutations within the gene encoding BAFF-R can influence its function and signaling efficiency, contributing to variations in immune responses and predisposition to diseases.

Function and Biological Significance

The primary functions of TNFRSF13C are related to B cell maturation, survival, and immune regulation. As the main receptor for BAFF, TNFRSF13C is crucial in various biological processes within the immune system:

B Cell Maturation and Survival:

• TNFRSF13C plays a pivotal role in transitioning immature B cells into mature B cells, a process that occurs primarily in the spleen and other peripheral lymphoid organs. BAFF-R signaling is required for B cells to pass through the transitional stage and become fully functional.
• By activating the NF-κB2 pathway, BAFF-R signaling supports B cell survival. NF-κB2 activation leads to gene expression that prevents apoptosis, allowing B cells to survive and become part of the functional immune repertoire.

Immune Regulation and Tolerance:

• TNFRSF13C is also involved in immune tolerance by regulating autoreactive B cells. Proper BAFF-R signaling helps control B cell selection, ensuring that autoreactive B cells are less likely to mature, which reduces the risk of autoimmune responses.
• By maintaining immune tolerance, BAFF-R prevents excessive or inappropriate immune responses that could target self-antigens, a feature crucial for preventing autoimmune diseases.

Interplay with TACI and BCMA:

• TNFRSF13C, TACI, and BCMA work in coordination to regulate B cell responses to BAFF. While BAFF-R is essential for the survival of transitional and naive B cells, TACI and BCMA contribute to the regulation of plasma cells and antibody production, ensuring a balanced immune response.

Clinical Issues

Autoimmune Diseases:

• Dysregulation of BAFF and BAFF-R signaling is associated with autoimmune diseases, including Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Multiple Sclerosis (MS). In these conditions, increased BAFF levels overstimulate BAFF-R, leading to the survival of autoreactive B cells that may attack the body’s own tissues.
• Therapeutic targeting of BAFF, such as with the monoclonal antibody belimumab, has shown efficacy in reducing disease activity in SLE. By inhibiting BAFF, this treatment reduces BAFF-R signaling, thereby decreasing the survival of autoreactive B cells.

Immunodeficiencies:

• Mutations or polymorphisms in the TNFRSF13C gene can lead to immunodeficiency disorders, most notably Common Variable Immunodeficiency (CVID). In CVID, defects in BAFF-R signaling impair B cell maturation, leading to low immunoglobulin levels and increased susceptibility to infections.
• In individuals with CVID, the impaired BAFF-R signaling prevents proper B cell survival and differentiation, resulting in a limited and ineffective B cell population that compromises adaptive immunity.

Cancer:

• While TNFRSF13C itself is not typically implicated in cancers, dysregulation of BAFF and its receptors has been associated with certain B cell malignancies, including non-Hodgkin lymphoma and chronic lymphocytic leukemia (CLL). BAFF-R signaling contributes to the survival and proliferation of malignant B cells in these cancers, where high BAFF levels support the survival of cancerous B cells.
• Targeting BAFF-R in B cell malignancies is an area of ongoing research, with the aim to disrupt survival signaling in malignant cells and reduce tumor growth.

Summary

TNFRSF13C, or BAFF-R, is a member of the tumor necrosis factor receptor superfamily and is the primary receptor for the B cell-activating factor (BAFF). Structurally, BAFF-R has a single cysteine-rich domain for binding BAFF, a transmembrane domain, and an intracellular domain that activates survival pathways upon ligand binding. BAFF-R signaling through the NF-κB2 pathway is essential for B cell survival, maturation, and immune regulation, especially in the transition of immature B cells into functional components of the adaptive immune system.

Dysregulation of TNFRSF13C can lead to autoimmune diseases, where excessive BAFF-R signaling supports the survival of autoreactive B cells, contributing to conditions like SLE and RA. In contrast, deficiencies in BAFF-R function can lead to immunodeficiencies like CVID, characterized by impaired B cell maturation and antibody production. TNFRSF13C is also relevant in certain B cell malignancies, where BAFF-R signaling may support the survival of malignant cells. Consequently, therapeutic strategies targeting BAFF-R and its ligands are being explored for autoimmune diseases and B cell cancers, with treatments such as belimumab showing promise in modulating immune responses.

In summary, TNFRSF13C is integral to B cell biology, with its regulation of survival and maturation playing a vital role in both health and disease.