TRAF2 Differentially Regulates the Canonical and Noncanonical Pathways of NF-κB Activation in Mature B Cells

Grech, Adrian P.; Amesbury, Michelle; Chan, Tyani D.; Gardam, Sandra; Basten, Antony; Brink, Robert

doi:10.1016/j.immuni.2004.09.011

Cited by 209 publications

(261 citation statements)

References 40 publications

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“…In cIAP1 or TRAF2 knock-out cells NIK levels are therefore constitutively high (6,12) and can be reduced by re-introduction of wild-type cIAP1 (Fig. 3A) or TRAF2 (18), respectively.…”

Section: Ring Functions Are Required For Ciap1 To Inhibit Activation mentioning

confidence: 99%

“…Receptor engagement results in lysosomal mediated degradation of TRAF2 and cIAP1 and activation of non-canonical NF-B resulting from NIK stabilization and subsequent processing of p100 to the active NF-B subunit p52 (7,10,11). In support of this idea, TRAF2 or cIAP1 knock-out MEFs were shown to have high constitutive levels of p52 and low levels of p100 compared with wild-type cells (6,12). cIAPs also play an important role at the TNF-R1 signaling complex in TNF-induced activation of canonical NF-B.…”

mentioning

confidence: 91%

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Tumor Necrosis Factor (TNF) Signaling, but Not TWEAK (TNF-like Weak Inducer of Apoptosis)-triggered cIAP1 (Cellular Inhibitor of Apoptosis Protein 1) Degradation, Requires cIAP1 RING Dimerization and E2 Binding

Feltham

Moulin

Vince

et al. 2010

Journal of Biological Chemistry

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Cellular inhibitor of apoptosis (cIAP) proteins, cIAP1 and cIAP2, are important regulators of tumor necrosis factor (TNF) superfamily (SF) signaling and are amplified in a number of tumor types. They are targeted by IAP antagonist compounds that are undergoing clinical trials. IAP antagonist compounds trigger cIAP autoubiquitylation and degradation. The TNFSF member TWEAK induces lysosomal degradation of TRAF2 and cIAPs, leading to elevated NIK levels and activation of non-canonical NF-B. To investigate the role of the ubiquitin ligase RING domain of cIAP1 in these pathways, we used cIAP-deleted cells reconstituted with cIAP1 point mutants designed to interfere with the ability of the RING to dimerize or to interact with E2 enzymes. We show that RING dimerization and E2 binding are required for IAP antagonists to induce cIAP1 degradation and protect cells from TNF-induced cell death. The RING functions of cIAP1 are required for full TNF-induced activation of NF-B, however, delayed activation of NF-B still occurs in cIAP1 and -2 double knock-out cells. The RING functions of cIAP1 are also required to prevent constitutive activation of non-canonical NF-B by targeting NIK for proteasomal degradation. However, in cIAP double knock-out cells TWEAK was still able to increase NIK levels demonstrating that NIK can be regulated by cIAP-independent pathways. Finally we show that, unlike IAP antagonists, TWEAK was able to induce degradation of cIAP1 RING mutants. These results emphasize the critical importance of the RING of cIAP1 in many signaling scenarios, but also demonstrate that in some pathways RING functions are not required. Cellular inhibitors of apoptosis (cIAPs)5 were identified as proteins that bound directly to the adaptor protein TRAF2, which in turn binds to tumor necrosis factor receptor 2 (TNF-R2) (1). cIAPs have three baculoviral IAP repeat domains and interaction of cIAP1 with TRAF2 is dependent on residues within the N-terminal, baculoviral IAP repeat 1 (BIR1) (2, 3). cIAP1 and cIAP2 also bear a C-terminal RING E3 ligase domain, and it is this domain that is required for IAP antagonist compound (IAC)-induced autoubiquitylation and proteasomal degradation (4 -7). cIAPs control activation of the NF-B family of transcription factors in both unstimulated and cytokinetreated cells. In the absence of cytokines, together with TRAF2 and TRAF3, cIAPs ubiquitylate and promote proteasomal degradation of NF-B inducing kinase (NIK), thereby preventing NIK from activating NF-B2. Consistent with a central role for cIAPs in these processes, antagonism of IAPs by IACs is sufficient to activate the non-canonical NF-B pathway through NIK stabilization and processing of p100 to p52 (6 -9).TNF-like weak inducer of apoptosis (TWEAK) binding to its receptor Fn14 is a physiological activator of NF-B. Receptor engagement results in lysosomal mediated degradation of TRAF2 and cIAP1 and activation of non-canonical NF-B resulting from NIK stabilization and subsequent processing of p100 to the active NF-B subunit p52 (7,10,11). In...

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“…In cIAP1 or TRAF2 knock-out cells NIK levels are therefore constitutively high (6,12) and can be reduced by re-introduction of wild-type cIAP1 (Fig. 3A) or TRAF2 (18), respectively.…”

Section: Ring Functions Are Required For Ciap1 To Inhibit Activation mentioning

confidence: 99%

mentioning

confidence: 91%

Tumor Necrosis Factor (TNF) Signaling, but Not TWEAK (TNF-like Weak Inducer of Apoptosis)-triggered cIAP1 (Cellular Inhibitor of Apoptosis Protein 1) Degradation, Requires cIAP1 RING Dimerization and E2 Binding

Feltham

Moulin

Vince

et al. 2010

Journal of Biological Chemistry

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“…TRAF2 is known to dampen specific signaling pathways triggered by TNFR1 (23). Furthermore, TRAF2 has been implicated as an inhibitor of Th2 responses through its interaction with NFAT-interacting protein 45 and as a negative regulator of the noncanonical pathway of NF-B activation in mature B cells (52,53). Whether TRAF2 negatively regulates signaling beyond competing with other signaling proteins for GITR binding is unclear.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid-Induced TNF Receptor, a Costimulatory Receptor on Naive and Activated T Cells, Uses TNF Receptor-Associated Factor 2 in a Novel Fashion as an Inhibitor of NF-κB Activation

Esparza

Arch

2005

The Journal of Immunology

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Glucocorticoid-induced TNFR (GITR) has been implicated as an essential regulator of immune responses to self tissues and pathogens. We have recently shown that GITR-induced cellular events promote survival of naive T cells, but are insufficient to protect against activation-induced cell death. However, the molecular mechanisms of GITR-induced signal transduction that influence physiologic and pathologic immune responses are not well understood. TNFR-associated factors (TRAFs) are pivotal adapter proteins involved in signal transduction pathways of TNFR-related proteins. Yeast two-hybrid assays and studies in HEK293 cells and primary lymphocytes indicated interactions between TRAF2 and GITR mediated by acidic residues in the cytoplasmic domain of the receptor. GITR-induced activation of NF-κB is blocked by A20, an NF-κB-inducible protein that interacts with TRAFs and functions in a negative feedback mechanism downstream of other TNFRs. Interestingly, in contrast with its effects on signaling triggered by other TNFRs, our functional studies revealed that TRAF2 plays a novel inhibitory role in GITR-triggered NF-κB activation.

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“…Taken together, these results suggest that TRAF3 may constitutively inhibit NF-κB2 activation and promote PKCδ nuclear translocation to induce spontaneous apoptosis in peripheral B cells (depicted in Figure 1). Similarly, resting splenic B cells from a conditional TRAF2 -/-mouse strain also show improved survival and higher levels of nuclear NF-κB2 ex vivo in the absence of stimuli [10]. Further experiments using TACI-Ig or BAFF-Ig, or alternatively, breeding conditional TRAF2 -/-mice with BAFF -/-or BAFF-R -/-mice are required to determine whether TRAF2-mediated inhibition of B cell survival is downstream of BAFF/APRIL signaling or a constitutive TRAF2 function.…”

Section: Constitutive Functions Of Traf Molecules In B Cellsmentioning

confidence: 96%

“…However, in contrast to TRAF3, TRAF2 overexpression in B cells promotes B cell activation [4], and B cell lines lacking TRAF2 show defects in JNK activation, Ig production, and CD40-BCR synergy (reviewed in [9]. Mice conditionally deficient in B cell TRAF2 show enhanced B cell survival and constitutive activation of the non-canonical NF-κB2 pathway, but this may be due to effects on signaling via other TNFR superfamily members (see below); the B cells do show reduced CD40-induced proliferation [10]. Another interesting function of TRAF2 revealed by TRAF2 -/-B cell lines is its role as the "master regulator" of CD40-mediated degradation of both itself and TRAF3 [11,12].…”

Section: Cd40mentioning

confidence: 99%

Roles of TRAF molecules in B lymphocyte function

Xie

Kraus

Stunz

et al. 2008

Cytokine & Growth Factor Reviews

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Tumor necrosis factor receptor associated factors (TRAFs) play a variety of interesting and important roles in the regulation of B lymphocyte function. They act both as cytoplasmic regulatory molecules, and as signal transducers for receptors involved in both innate and adaptive humoral immune responses. In this brief review, we highlight the current state of knowledge of the diverse roles of TRAF molecules in the functions of B lymphocytes. CD40CD40 is the most well-studied member of the TNFR superfamily expressed by B lymphocytes, so its interactions with TRAF molecules have also been intensively investigated. B cell CD40 is important in the induction of B cell survival and expansion, immunoglobulin (Ig) production and isotype switching, upregulation of surface molecules involved in B cell antigen presentation, differentiation to B memory cells, and the production of various cytokines (reviewed in [1]. The TRAF molecules have been shown to contribute to each of these functions (reviewed in [2].In 1994, TRAF3 became the first cytoplasmic molecule demonstrated to associate with CD40 (reviewed in [2]). However, for many years, its roles in CD40 signaling were largely unknown, and are still not completely understood. TRAF3 -/-mice die shortly after birth, but adoptive transfer of fetal liver cells from these mice suggested that their B cells were capable of reconstituting the humoral response [3], implying that TRAF3 is not required to promote CD40-mediated antibody responses. This conclusion was supported by experiments in B cell lines demonstrating that inducible overexpression of TRAF3 inhibits both CD40 responses [4], and cooperation between CD40 and the BCR [5]. Subsequently, B cell lines made completely TRAF3-deficient via gene targeting by homologous recombination show no defects in CD40 signaling overall, and display enhanced CD40-mediated c-jun kinase (JNK) activation and IgM production [6]. Recently, mice made conditionally deficient in TRAF3 only in CD19+ B cells show no deficiencies in CD40 signaling in vitro and have enhanced antibody responses [7]. TRAF2 was initially demonstrated to bind CD40 by exogenous overexpression studies in adenocarcinoma cell lines, in which it promotes JNK activation and the activity of NF-κB reporter genes (reviewed in [2]. Because TRAF2 -/-mice have an early lethal phenotype [8],Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers

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TRAF2 Differentially Regulates the Canonical and Noncanonical Pathways of NF-κB Activation in Mature B Cells

Cited by 209 publications

References 40 publications

Tumor Necrosis Factor (TNF) Signaling, but Not TWEAK (TNF-like Weak Inducer of Apoptosis)-triggered cIAP1 (Cellular Inhibitor of Apoptosis Protein 1) Degradation, Requires cIAP1 RING Dimerization and E2 Binding

Tumor Necrosis Factor (TNF) Signaling, but Not TWEAK (TNF-like Weak Inducer of Apoptosis)-triggered cIAP1 (Cellular Inhibitor of Apoptosis Protein 1) Degradation, Requires cIAP1 RING Dimerization and E2 Binding

Glucocorticoid-Induced TNF Receptor, a Costimulatory Receptor on Naive and Activated T Cells, Uses TNF Receptor-Associated Factor 2 in a Novel Fashion as an Inhibitor of NF-κB Activation

Roles of TRAF molecules in B lymphocyte function

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