Abstract
The B cell survival factor (TNFSF13B/BAFF) is often elevated in autoimmune diseases and is targeted in the clinic for the treatment of systemic lupus erythematosus. BAFF contains a loop region designated the flap, which is dispensable for receptor binding. Here we show that the flap of BAFF has two functions. In addition to facilitating the formation of a highly active BAFF 60-mer as shown previously, it also converts binding of BAFF to TNFRSF13C (BAFFR) into a signaling event via oligomerization of individual BAFF-BAFFR complexes. Binding and activation of BAFFR can therefore be targeted independently to inhibit or activate the function of BAFF. Moreover, structural analyses suggest that the flap of BAFF 60-mer temporarily prevents binding of an anti-BAFF antibody (belimumab) but not of a decoy receptor (atacicept). The observed differences in profiles of BAFF inhibition may confer distinct biological and clinical efficacies to these therapeutically relevant inhibitors.
Highlights
The B cell survival factor (TNFSF13B/BAFF) is often elevated in autoimmune diseases and is targeted in the clinic for the treatment of systemic lupus erythematosus
Recombinant wild type (WT) and flap mutant BAFF, FLAGtagged or naturally cleaved, were size-fractionated to recover 3mers, quantified by western blot (Fig. 1b, c) and found to all bind immobilized recombinant receptors (BAFFR, TACI, and BCMA) (Fig. 1d). This result was confirmed in a competitive enzyme-linked immunosorbent assay (ELISA) where FLAGtagged WT or mutant BAFF competed with naturally cleaved untagged WT BAFF for receptor binding
WT and mutant BAFF bound identically to endogenous BAFF to TNFRSF13C (BAFFR) on BJAB Burkitt lymphoma cells, and to TACI expressed in BAFFR-ko BJAB cells (Supplementary Fig. 1)
Summary
The B cell survival factor (TNFSF13B/BAFF) is often elevated in autoimmune diseases and is targeted in the clinic for the treatment of systemic lupus erythematosus.
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