Gardam, S., Sierro, F., Basten, A., Mackay, F. & Brink, R. TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor. Immunity 28, 391-401

Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst NSW 2010, Australia.
Immunity (Impact Factor: 21.56). 04/2008; 28(3):391-401. DOI: 10.1016/j.immuni.2008.01.009
Source: PubMed


Tumor necrosis factor receptor-associated factors 2 and 3 (TRAF2 and TRAF3) were shown to function in a cooperative and nonredundant manner to suppress nuclear factor-kappaB2 (NF-kappaB2) activation, gene expression, and survival in mature B cells. In the absence of this suppressive activity, B cells developed independently of the obligatory B cell survival factor, BAFF (B cell-activating factor of the tumor necrosis factor family). However, deletion of either TRAF2 or TRAF3 from the T cell lineage did not promote T cell survival, despite causing extensive NF-kappaB2 activation. This constitutive, lineage-specific suppression of B cell survival by TRAF2 and TRAF3 determines the requirement for BAFF to sustain B cell development in vivo. Binding of BAFF to BAFF receptor reversed TRAF2-TRAF3-mediated suppression of B cell survival by triggering the depletion of TRAF3 protein. This process was TRAF2 dependent, revealing dual roles for TRAF2 in regulating B cell homeostasis.

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    • "Deletion of liver TRAF3 in adult obese mice attenuates insulin resistance, hyperglycemia, and glucose intolerance To determine whether aberrant levels of hepatic TRAF3 contribute to metabolic disorders in obesity, we generated and metabolically characterized mice with liver-specific deletion of TRAF3. TRAF3 f/f mice, in which the TRAF3 gene is flanked by two loxp sites, have been described previously [10,26]. TRAF3 f/f male mice were fed a HFD for 8 weeks to induce obesity. "
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    ABSTRACT: Metabolic inflammation is believed to promote insulin resistance and type 2 diabetes progression in obesity. TRAF3, a cytoplasmic signaling protein, has been known to mediate/modulate cytokine signaling in immune cells. The goal is to define the metabolic function of hepatic TRAF3 in the setting of obesity.
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    • "No direct interaction between cIAP1/2 and TRAF3 has ever been shown, which suggests that TRAF2 plays a dual role in this process: it both recruits the ubiquitin ligase, cIAP1/2 to its target, TRAF3 via direct interaction with both proteins, as well as activating cIAP1/2, by K63 ubiquitylation, which optimizes the subsequent K48 ubiquitylation and degradation of TRAF3. It is likely a similar process occurs at the BAFFR and this is supported by in vivo evidence showing that TRAF3 is not efficiently degraded in TRAF2-deficient B cells, which express BAFFR and are subject to continual BAFFR ligation (43). It is not currently understood how the K63 polyubiquitination of cIAP1/2 promotes its own K48 ubiquitylation activity. "
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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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    • "We and others previously reported that B cell-specific loss of the traf3 gene enhances the survival of B cells independent of cell proliferation (9, 10). We also demonstrated that this enhanced B cell-specific survival renders B cells independent of the soluble factor BAFF, and results in constitutive activation of the non-canonical NF-κB2 pathway (9). "
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    ABSTRACT: The adaptor protein TRAF3 restrains B cell activating factor receptor (BAFFR) and CD40-mediated activation of the NF-κB2 pathway in B cells. Mice lacking TRAF3 specifically in B cells revealed the critical role of TRAF3 in restraining homeostatic B cell survival. Furthermore, loss-of-function mutations of the traf3 gene have been associated with human B cell malignancies, especially multiple myeloma (MM). It has been proposed that receptor-induced TRAF3 degradation leads to stabilization of the NF-κB inducing kinase (NIK), and subsequent NF-κB2 activation. However, it is unclear how receptor-mediated TRAF3 degradation or loss-of-function contributes to B cell-specific NF-κB2 activation. In the current study, we employed two complementary models to address this question. One utilized a mutant traf3 gene found in a human MM-derived cell line called LP1. The LP1 mutant TRAF3 protein lacks the TRAF-N and TRAF-C domains. Consistent with the paradigm described, expression of LP1 TRAF3 in B cells promoted higher basal levels of NF-κB2 activation compared to Wt TRAF3. However, LP1 did not associate with TRAF2, CD40, or BAFFR, and no LP1 degradation was observed following receptor engagement. Interestingly, LP1 showed enhanced NIK association. Thus, TRAF3 degradation becomes dispensable to activate NF-κB2 when it is unable to associate with TRAF2. In a second model, we examined several mutant forms of BAFFR that are unable to induce NF-κB2 activation in B cells. Signaling to B cells by each of these BAFFR mutants, however, induced levels of TRAF3 degradation similar to those induced by Wt BAFFR. Thus, in B cells, receptor-mediated TRAF3 degradation is not sufficient to promote NF-κB2 activation. We thus conclude that there is not a simple linear relationship in B lymphocytes between relative levels of cellular TRAF3, induced TRAF3 degradation, NIK activation, and NF-κB2 activation.
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