γ-secretase directly sheds the survival receptor BCMA from plasma cells

Abstract

Survival of plasma cells is regulated by B-cell maturation antigen (BCMA), a membrane-bound receptor activated by its agonist ligands BAFF and APRIL. Here we report that γ-secretase directly cleaves BCMA, without prior truncation by another protease. This direct shedding is facilitated by the short length of BCMA's extracellular domain. In vitro, γ-secretase reduces BCMA-mediated NF-κB activation. In addition, γ-secretase releases soluble BCMA (sBCMA) that acts as a decoy neutralizing APRIL. In vivo, inhibition of γ-secretase enhances BCMA surface expression in plasma cells and increases their number in the bone marrow. Furthermore, in multiple sclerosis, sBCMA levels in spinal fluid are elevated and associated with intracerebral IgG production; in systemic lupus erythematosus, sBCMA levels in serum are elevated and correlate with disease activity. Together, shedding of BCMA by γ-secretase controls plasma cells in the bone marrow and yields a potential biomarker for B-cell involvement in human autoimmune diseases.

Analysis of serum B cell‐activating factor from the tumor necrosis factor family (BAFF) and its soluble receptors in systemic lupus erythematosus

“…The presence of sBAFF‐R in human SLE sera has not previously been described. The present study confirmed the presence of both sTACI and sBCMA in sera from SLE patients, in a larger and better‐defined cohort than previously reported . Both serum sTACI and sBCMA, but not sBAFF‐R, were significantly higher in SLE than in HC.…”

“…Serum concentrations of BAFF were also increased in SLE compared to HC, but this association was attenuated after adjusting for age and ethnicity. Higher serum sTACI and sBCMA concentrations were previously reported in SLE . It is noteworthy that no significant association was found between serum BAFF and any of its soluble receptors in SLE in the present study.…”

“…When further cleaved by γ‐secretase, sTACI can oligomerise to act as a decoy receptor for both BAFF and APRIL . The same group also reported the presence of a soluble form of BCMA (sBCMA) in human sera, produced from cleavage of BCMA from plasma cells by γ‐secretase, which in vitro acts as a decoy receptor specific for APRIL . The same group showed that sBCMA can also be shed by plasmacytoid dendritic cells via a similar γ‐secretase‐dependent cleavage .…”

Non‐cell‐autonomous function of DR6 in Schwann cell proliferation

“…Peschon et al, 1998;McIlwain et al, 2012;Laurent et al, 2015), we now report that DR6 is a striking exception. While for most TNFRSF members the protease-mediated shedding is a mechanism to terminate their receptor function (e.g.…”

BAFF inhibition in SLE—Is tolerance restored?

“…40,41 Nevertheless, TACI serves to maintain BLIMP-1 expression and thus supports the differentiation and survival of long-lived plasma cells. [43][44][45] In contrast to mice, humans express both short and long isoforms of TACI. 40,41 In addition to a direct regulatory function, loss of surface TACI or of the soluble decoy receptor may account for B cell hyperplasia because of reciprocally increased serum BAFF and APRIL levels.…”