BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells

Summary: B cell activating factor (BAFF) provides B cells with essential survival signals. It binds to three receptors: BAFFR, TACI, and BCMA that are differentially expressed by B cell subsets. BAFFR is early expressed in circulating B cells and provides key signals for further maturation. Here, we report that highly regulated BAFFR processing events modulate BAFF responses. BAFFR processing is triggered by BAFF binding in B cells co-expressing TACI and it is executed by the metalloproteases ADAM10 and ADAM17. The degree of BAFF oligomerization, the expression of ADAM proteins in different B cell subsets, and the activation status of the cell determine the proteases involved in BAFFR processing. Inhibition of ADAM10 augments BAFF-dependent survival of primary human B cells, whereas inhibition of ADAM17 increases BAFFR expression levels on germinal center B cells. Therefore, BAFF-induced processing of BAFFR regulates BAFF-mediated B cell responses in a TACI-dependent manner. : Smulski et al. report that the B cell survival receptor BAFFR undergoes ligand-induced shedding but only in cells co-expressing a second receptor for BAFF called TACI. BAFFR shedding can be performed by ADAM10 in circulating B cells or by ADAM17 in germinal center B cells and limits BAFF-mediated survival signals. Keywords: B cell, BAFF-receptor, BAFFR, TACI, ADAM10, ADAM17, metalloprotease, processing, ectodomain shedding, germinal center, survival