The Role of BANK1 in B Cell Signaling and Disease

Abstract

The B cell scaffold protein with ankyrin repeats (BANK1) is expressed primarily in B cells and with multiple but discrete roles in B cell signaling, including B cell receptor signaling, CD40-related signaling, and Toll-like receptor (TLR) signaling. The gene for BANK1, located in chromosome 4, has been found to contain genetic variants that are associated with several autoimmune diseases and also other complex phenotypes, in particular, with systemic lupus erythematosus. Common genetic variants are associated with changes in BANK1 expression in B cells, while rare variants modify their capacity to bind efferent effectors during signaling. A BANK1-deficient model has shown the importance of BANK1 during TLR7 and TLR9 signaling and has confirmed its role in the disease. Still, much needs to be done to fully understand the function of BANK1, but the main conclusion is that it may be the link between different signaling functions within the B cells and they may act to synergize the various pathways within a cell. With this review, we hope to enhance the interest in this molecule.

Keywords: B cell receptor; B cell scaffold with ankyrin repeats; B cells; BLK; CD40; LYN; TLR7; TRAF6; autoimmunity; genetic association.

Figure 1

Model of the role of BANK1 in B cell signaling. BANK1 is primarily expressed in B cells and is involved in B cell signaling pathways. During BCR activation, BANK1 becomes tyrosine phosphorylated and binds the Src family kinases LYN and BLK (1-2) [1]. BANK1 also interacts with PLC-γ2 [44], regulating BCR-induced calcium mobilization. BANK1 attenuates CD40-mediated AKT activation (4) [45]. Following the PI3K/AKT pathway, the transcription factors FOXO1 and AICDA appear to increase in subjects with BANK1 risk variants, resulting in an increase in plasma cells, memory B cells, and germinal center B cells (5) [38]. BANK1 interacts with TRAF6 and MyD88 through endosomal TLR7 activation (6), triggering an IRF7-dependent production of IFNα and several proinflammatory cytokines. In the absence of exon 2, in BANK1–D2, there is a significant decrease in binding to MyD88 compared to BANK1–FL [37]. Finally, BANK1 binds to TRAF6, forming a complex with the sequestosome protein p62 and the deubiquitinating enzyme CYLD. In these structures, BANK1 promotes TRAF6 sequestration, diminishing IRF5 activation and type I IFN induction, and this is modified by a mutation in the amino acid position 40 in exon 2 (W40C) (7) [20].