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.

A20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-κB signaling in response to specific proinflammatory stimuli in different cell types and has been suggested as a susceptibility gene for rheumatoid arthritis. To define the contribution of A20 to rheumatoid arthritis pathology, we generated myeloid-specific A20-deficient mice and show that specific ablation of Tnfaip3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis. Myeloid-A20-deficient mice have high levels of inflammatory cytokines in their serum, consistent with a sustained NF-κB activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 and IL-6 dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. Together, these observations indicate a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis, supporting the idea of developing A20 modulatory drugs as cell-targeted therapies.

IntroductionB cells play essential roles during protective immune responses to invading pathogens. On encounter of foreign antigen and with cognate T-cell help, B lymphocytes proliferate and form distinct histologic structures, termed germinal center (GC). In the GC, they undergo somatic hypermutation and class-switch recombination. During somatic hypermutation, they introduce random mutations into their immunoglobulin variable regions while they exchange the heavy chain constant region during class-switch recombination to allow for different effector functions. After a selection process by antigen, B cells differentiate into memory B cells and plasma cells (PCs), which secrete antibodies. 1 The deregulation of this process is heavily implicated in human disease. Production of class-switched antibodies against self-antigens causes or contributes to various autoimmune syndromes and unrestrained B-cell proliferation and survival can result in lymphomas. 1,2 It is thought that the majority of human lymphomas derive from the GC, probably because the DNA damage inherent to the GC reaction facilitates mutations and chromosomal translocations. 1,3 Recently, the ubiquitin-editing enzyme A20, encoded by the tumor necrosis factor-␣-inducible gene 3 (TNFAIP3), has been associated with both autoimmunity and lymphomagenesis. Polymorphisms and mutations in or near the TNFAIP3 genomic locus have been linked with various human autoimmune syndromes with a strong humoral component, such as systemic lupus erythematosus (SLE), 4,5 rheumatoid arthritis, 6,7 and celiac disease. 8 Loss of A20 function through mutations, chromosomal deletions, and/or promoter methylation is a frequent event in several human lymphomas, 9-12 all of which are characterized by constitutive activation of nuclear factor-B (NF-B). 13 These factors regulate a plethora of genes encoding for proinflammatory mediators, antiapoptotic proteins, cell adhesion molecules and, for negative feedback control, inhibitory proteins, such as p100, IB␣, and A20. 14,15 During the transmission of NF-B activating signals from cell-surface receptors such as the B-cell receptor (BCR), CD40, or Toll-like receptors (TLRs), signal transduction occurs via the attachment of polyubiquitin chains to key proteins, including MALT1 or TRAF6. Polyubiquitin chains, linked via K63 or linear assembly, serve to recruit different kinase complexes. In the case of canonical NF-B, induced proximity allows the upstream kinase TAK1 to phosphorylate its target IKK2, which then effects NF-B activation. A20, whose transcription is induced by NF-B, dampens signaling through 2 main activities. First, as deubiquitinase A20 removes K63-linked polyubiquitin chains from essential signaling intermediates, such as TRAF6. Second, A20 induces, in concert with other proteins, degradation of some of its molecular targets, through addition of K48-linked ubiquitin chains. 14,16 Degradation of RIP1 limits TNF-induced signaling, 14 whereas degradation of the K63-chain-specific E2 ligases Ubc13/UbcH5c generally affects t...

A20 is a nuclear factor κB (NF-κB) target gene that encodes a ubiquitin-editing enzyme that is essential for the termination of NF-κB activation after tumor necrosis factor (TNF) or microbial product stimulation and for the prevention of TNF-induced apoptosis. Mice lacking A20 succumb to inflammation in several organs, including the intestine, and A20 mutations have been associated with Crohn’s disease. However, ablation of NF-κB activity, specifically in intestinal epithelial cells (IECs), promotes intestinal inflammation. As A20 deficiency sensitizes cells to TNF-induced apoptosis yet also promotes NF-κB activity, it is not clear if A20 deficiency in IECs would exacerbate or ameliorate intestinal inflammation. We generated mice lacking A20 specifically in IECs. These mice did not show spontaneous intestinal inflammation but exhibited increased susceptibility to experimental colitis, and their IECs were hypersensitive to TNF-induced apoptosis. The resulting TNF-driven breakdown of the intestinal barrier permitted commensal bacterial infiltration and led to systemic inflammation. These studies define A20 as a major antiapoptotic protein in the intestinal epithelium and further indicate that defects in A20 might contribute to inflammatory bowel disease in humans.