B Cell Activating Factor Signaling

Tumor Necrosis Factor (TNF) family of cytokines play important roles in various physiological and pathological processes, including cell proliferation, differentiation, apoptosis, modulation of immune response, and induction of inflammation. B-Cell Activating Factor (BAFF) is a TNF-related ligand that promotes B-Cell survival. It is expressed on dendritic cells, monocytes/macrophages, and T-Cells. BAFF is a positive regulator of B-Cell function, with effects on cell survival, activation, and differentiation. BAFF is found as homotrimer membrane-bound form in T-Cells and in a soluble form after cleavage by furin-type convertases that is released from the cell to stimulate B-Cell proliferation and differentiation. BAFF binds to three receptors: BCMA (B-Cell Maturation Antigen), TACI (Transmembrane Activator and Cyclophilin Ligand Interactor) and BAFFR (BAFF Receptor). Expression of BCMA and BAFFR is B-Cell specific, whereas TACI can be found on B-Cells and on subsets of activated T cells. Moreover, BAFF shares two receptors TACI and BCMA with another TNF-like ligand named APRIL (A Proliferation-Inducing Ligand), which is involved in tumor cell growth.BCMA is a 25kDa glycolipid anchored protein. The N-terminal part of proteins contains a conserved six-cysteine motif. The six-cysteine motif of BCMA is not the canonical motif of TNFRs (TNF Receptors) but corresponds to a variant motif present in the fourth repeat of the TNFRI molecule. BCMA can activate the transcription factor NF-κB (Nuclear Factor-κB) through TRAF5 (TNF Receptor-Associated Factor-5), TRAF6 (TNF Receptor-Associated Factor-6), TRAF3 (TNF Receptor-Associated Factor-3), NIK (NF-κB Inducing Kinase), and IKK (I-κB Kinase) dependent pathway. Engagement of BCMA also activates JNK (Jun N-terminal Kinases), p38 MAPK (Mitogen Activated Protein Kinase) and the transcription factor Elk1. The intracellular domain of TACI associates with TRAFs and activates NF-κB, NFAT (Nuclear Factor of Activated T-Cells) and JNK, thus presumably transducing signals for B-Cell proliferation and survival. BAFFR contains only four cysteine residues in its extracellular or ligand binding domain, making it the smallest CRD (Cysteine-Rich Domain) in the TNF receptor family. The binding of BAFF to BAFFR is primarily responsible for supporting transitional B-Cell maturation and enhancing the survival of mature B-Cells. Increased BAFF-mediated B-Cell survival has also been shown to enhance humoral immune responses. The identification of BCMA as a NF-κB-activating receptor for BAFF suggests molecular targets for drug development against certain immunodeficient or autoimmune diseases. Manipulation of the BAFF/BCMA-signaling system may provide novel approaches for modulation of B-Cell mediated immune responses and autoimmune diseases, such as Lupus and rheumatoid arthritis.