APRIL Pathway

APRIL, also known as TALL2 (TNF- and APOL-related Leukocyte expressed Ligand-2), has no essential function in normal B-cell development and plays only a minor role in B-cell homeostasis. In immune responses, APRIL acts as a costimulator for B- and T-cell proliferation and supports class switching. In general, cytokines of the TNF superfamily are functional both in their membrane-bound and in soluble form when shed by enzymatic cleavage from the surface through a furin-like convertase. APRIL is secreted following intracellular processing in the Golgi apparatus. APRIL binds to two separate receptors, the TACI (Transmembrane Activator and Calcium modulator ligand Interactor), and the BCMA (B Cell Maturation Antigen). Both receptors are expressed on B-cells, although their expression level changes with B-cell maturation (Ref. 2). These receptors are functional as their ligation triggers activation of NF-KappaB, MAPK/JNK and Akt signaling. APRIL may also induce apoptosis through its interaction with other TNF receptor family proteins such as TNFRSF6/FAS and TNFRSF14/HVEM.

Signaling through TACI in mature B-cells or plasmablasts is only achieved by higher-order APRIL oligomers, all of which are potent activators of a multimerization-dependent reporter signaling pathway. TACI intracellular domain interacts with TNFR-associated factor TRAF2, 5, and 6. TRAFs are trimeric intermediates in the signaling pathway of numerous TNF receptor family members. By bringing together the receptors, a trimeric ligand may allow recruitment to the complex of just one intracellular TRAF, which may not be enough to induce signaling, as oligomerization of trimeric TRAF-2 and TRAF-6 is required to activate downstream signaling events (Ref. 3). The cytoplasmic domain of TACI encompasses a conserved motif that binds MyD88, an adaptor that activates transcription factor NF-kB signaling pathways via a Toll–Interleukin 1 (IL-1) receptor (TIR) domain. TACI lacks a TIR domain, yet triggers CSR via the DNA-editing enzyme AID by activating NF-kB through Toll-like receptor (TLR)-like MyD88-IRAK1-IRAK4-TRAF6-TAK1 pathway (Ref. 4 and 5). BCMA binds to APRIL with high affinity. BCMA enhances B-cell antigen presentation by recruiting TRAF proteins and activating NF-KappaB. BCMA might regulate post-CSR events, including the differentiation and survival of mucosal IgA-secreting plasma cells (Ref. 6).