Morrison, M.D., Reiley, W., Zhang, M. & Sun, S.C. An atypical tumor necrosis factor (TNF) receptor-associated factor-binding motif of B cell-activating factor belonging to the TNF family (BAFF) receptor mediates induction of the noncanonical NF-B signaling pathway. J. Biol. Chem. 280, 10018-10024

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, Pennsylvania 17033, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2005; 280(11):10018-24. DOI: 10.1074/jbc.M413634200
Source: PubMed


BAFF receptor (BAFFR) is a member of the TNF receptor (TNFR) superfamily that regulates the survival and maturation of B cells. BAFFR exerts its signaling function by inducing activation of NF-kappaB, although the underlying mechanism has not been well defined. By using a chimeric BAFFR, we show that BAFFR preferentially induces the noncanonical NF-kappaB signaling pathway. This specific function of BAFFR is mediated by a sequence motif, PVPAT, which is homologous to the TRAF-binding site (PVQET) present in CD40, a TNFR known to induce both the canonical and noncanonical NF-kappaB pathways. Mutation of this putative TRAF-binding motif within BAFFR abolishes its interaction with TRAF3 as well as its ability to induce noncanonical NF-kappaB. Interestingly, modification of the PVPAT sequence to the typical TRAF-binding sequence, PVQET, is sufficient to render the BAFFR capable of inducing strong canonical NF-kappaB signaling. Further, this functional acquisition of the modified BAFFR is associated with its stronger and more rapid association with TRAF3. These findings suggest that the PVPAT sequence of BAFFR not only functions as a key signaling motif of BAFFR but also determines its signaling specificity in the induction of the noncanonical NF-kappaB pathway.

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Available from: Matt Morrison, Jul 28, 2015
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    • "Most BAFF bioassays developed so far have primarily utilized primary B-cells isolated from mouse spleen [12,13]. Proliferation and immune precipitation by Western blot are the typical assay readouts. "
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    ABSTRACT: BAFF has a critical role in B-cell survival, maturation and function, which makes its pathway a prime therapeutic target for various autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis and Sjögren's syndrome. A cell-based assay that measures the functional activity of BAFF is required for many high throughput purposes, such as lead target screening and BAFF quantification. We report here the development of a sensitive BAFF responsive cell line via stable transfection of the BAFFR-TNFR1 hybrid receptor into monkey kidney epithelial COS-1 cells. The cellular response to BAFF can be detected by measuring the secretion of IL-8. This BAFF bioassay is not only reproducible and sensitive, but also responsive to a wide concentration range of BAFF stimulation in sera from various species. This cell line is useful in the development of sensitive bioassays to measure the levels of bioactive BAFF, inhibition of BAFF and neutralizing antibodies against any BAFF pathway-mediated therapeutic proteins.
    Full-text · Article · Mar 2014
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    • "The extracellular interaction between BAFF and BAFFR facilitates the recruitment of TRAF3 to the cytoplasmic domain of BAFFR, via a PVPAT binding site (32) which is unable to recruit other TRAF family members (42). Following recruitment to BAFFR, TRAF3 undergoes proteasomal degradation (33), a process which requires TRAF2 and cIAP1/2. "
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    ABSTRACT: It has been more than a decade since it was recognized that the nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) transcription factor family was activated by two distinct pathways: the canonical pathway involving NF-κB1 and the non-canonical pathway involving NF-κB2. During this time a great deal of evidence has been amassed on the ligands and receptors that activate these pathways, the cytoplasmic adapter molecules involved in transducing the signals from receptors to nucleus, and the resulting physiological outcomes within body tissues. In contrast to NF-κB1 signaling, which can be activated by a wide variety of receptors, the NF-κB2 pathway is typically only activated by a subset of receptor and ligand pairs belonging to the tumor necrosis factor (TNF) family. Amongst these is B cell activating factor of the TNF family (BAFF) and its receptor BAFFR. Whilst BAFF is produced by many cell types throughout the body, BAFFR expression appears to be restricted to the hematopoietic lineage and B cells in particular. For this reason, the main physiological outcomes of BAFF mediated NF-κB2 activation are confined to B cells. Indeed BAFF mediated NF-κB2 signaling contributes to peripheral B cell survival and maturation as well as playing a role in antibody responses and long term maintenance plasma cells. Thus the importance BAFF and NF-κB2 permeates the entire B cell lifespan and impacts on this important component of the immune system in a variety of ways.
    Full-text · Article · Jan 2014 · Frontiers in Immunology
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    • "The binding of BLyS and APRIL to their receptors activates specific TNF receptor-associated factors (TRAFs), which regulate signal transduction in B cells [8] [9]. Beside their well-known function as antibody secreting cells, an antibody independent role for B-cells in disease pathogenesis has been documented by experimental data as well as the promising results of B-cell depleting therapies in RA [10] [11] [12]. "
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    ABSTRACT: Aim of the work To assess serum levels of B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) to determine their correlations with disease activity in pediatric systemic lupus erythematosus (pSLE) and juvenile idiopathic arthritis (JIA) patients. Patients and methods Twenty-nine pSLE patients and 33 JIA patients were recruited. SLE disease activity was assessed using the systemic lupus erythematosus disease activity index (SLEDAI), while the juvenile arthritis 27 joint disease activity score (JADAS-27) was calculated for JIA patients. Serum samples were assayed for BLyS and APRIL by the enzyme linked immunosorbent assay (ELISA). Results Serum BLyS and APRIL were elevated in both pSLE and JIA patients compared to controls. Serum BLyS levels correlated with both SLE and JIA disease activity (p = 0.042, p = 0.019, respectively) whereas serum APRIL levels correlated positively with JADAS-27 and inversely with SLEDAI (p = 0.001, p = 0.02, respectively). Elevated serum BLyS and APRIL were significantly associated with a lower incidence of nephritis (p = 0.043, p = 0.016, respectively), while elevated serum APRIL significantly associated with negative anti-dsDNA in pSLE patients (p = 0.017). In JIA patients, both serum BLyS and APRIL were significantly associated with the presence of ANA (p = 0.008, p < 0.001, respectively), while high serum APRIL associated with the presence of RF (p = 0.035). APRIL and BLYS levels correlated with each other positively in JIA but inversely in pSLE patients. Conclusion Serum BLyS showed elevated levels that correlated significantly with pSLE and JIA disease activity, accordingly anti-BLyS therapy might be of great benefit to offset disease flare. The inverse correlations observed between APRIL with both BLyS and disease activity in pSLE patients raises the possibility of being a down regulator of the disease process.
    Full-text · Article · Jan 2013 · Egyptian Rheumatologist
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