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1
Devergne, O., E. Hatzivassiliou, K. M. Izumi, K. M. Kaye, M. F. Kleijnen, E. Kieff, and G. Mosialos. "Association of TRAF1, TRAF2, and TRAF3 with an Epstein-Barr virus LMP1 domain important for B-lymphocyte transformation: role in NF-kappaB activation." Molecular and Cellular Biology 16, no. 12 (December 1996): 7098–108. http://dx.doi.org/10.1128/mcb.16.12.7098.
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The Epstein-Barr virus (EBV) transforming protein LMP1 appears to be a constitutively activated tumor necrosis factor receptor (TNFR) on the basis of an intrinsic ability to aggregate in the plasma membrane and an association of its cytoplasmic carboxyl terminus (CT) with TNFR-associated factors (TRAFs). We now show that in EBV-transformed B lymphocytes most of TRAF1 or TRAF3 and 5% of TRAF2 are associated with LMP1 and that most of LMP1 is associated with TRAF1 or TRAF3. TRAF1, TRAF2, and TRAF3 bind to a single site in the LMP1 CT corresponding to amino acids (aa) 199 to 214, within a domain which is important for B-lymphocyte growth transformation (aa 187 to 231). Further deletional and alanine mutagenesis analyses and comparison with TRAF binding sequences in CD40, in CD30, and in the LMP1 of other lymphycryptoviruses provide the first evidence that PXQXT/S is a core TRAF binding motif. The negative effects of point mutations in the LMP1(1-231) core TRAF binding motif on TRAF binding and NF-kappaB activation genetically link the TRAFs to LMP1(1-231)-mediated NF-kappaB activation. NF-kappaB activation by LMP1(1-231) is likely to be mediated by TRAF1/TRAF2 heteroaggregates since TRAF1 is unique among the TRAFs in coactivating NF-kappaB with LMP1(1-231), a TRAF2 dominant-negative mutant can block LMP1(1-231)-mediated NF-kappaB activation as well as TRAF1 coactivation, and 30% of TRAF2 is associated with TRAF1 in EBV-transformed B cells. TRAF3 is a negative modulator of LMP1(1-231)-mediated NF-kappaB activation. Surprisingly, TRAF1, -2, or -3 does not interact with the terminal LMP1 CT aa 333 to 386 which can independently mediate NF-kappaB activation. The constitutive association of TRAFs with LMP1 through the aa 187 to 231 domain which is important in NF-kappaB activation and primary B-lymphocyte growth transformation implicates TRAF aggregation in LMP1 signaling.
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Chin, Arnold I.-Dah, Junyan Shu, Chong Shan Shi, Zhengbin Yao, John H. Kehrl, and Genhong Cheng. "TANK Potentiates Tumor Necrosis Factor Receptor-Associated Factor-Mediated c-Jun N-Terminal Kinase/Stress-Activated Protein Kinase Activation through the Germinal Center Kinase Pathway." Molecular and Cellular Biology 19, no. 10 (October 1, 1999): 6665–72. http://dx.doi.org/10.1128/mcb.19.10.6665.
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ABSTRACT Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are mediators of many members of the TNF receptor superfamily and can activate both the nuclear factor κB (NF-κB) and stress-activated protein kinase (SAPK; also known as c-Jun N-terminal kinase) signal transduction pathways. We previously described the involvement of a TRAF-interacting molecule, TRAF-associated NF-κB activator (TANK), in TRAF2-mediated NF-κB activation. Here we show that TANK synergized with TRAF2, TRAF5, and TRAF6 but not with TRAF3 in SAPK activation. TRAF2 and TANK individually formed weak interactions with germinal center kinase (GCK)-related kinase (GCKR). However, when coexpressed, they formed a strong complex with GCKR, thereby providing a potential mechanism for TRAF and TANK synergy in GCKR-mediated SAPK activation, which is important in TNF family receptor signaling. Our results also suggest that TANK can form potential intermolecular as well as intramolecular interactions between its amino terminus and carboxyl terminus. This study suggests that TANK is a regulatory molecule controlling the threshold of NF-κB and SAPK activities in response to activation of TNF receptors. In addition, CD40 activated endogenous GCKR in primary B cells, implicating GCK family proteins in CD40-mediated B-cell functions.
3
Miller, William E., Jeanette L. Cheshire, and Nancy Raab-Traub. "Interaction of Tumor Necrosis Factor Receptor-Associated Factor Signaling Proteins with the Latent Membrane Protein 1 PXQXT Motif Is Essential for Induction of Epidermal Growth Factor Receptor Expression." Molecular and Cellular Biology 18, no. 5 (May 1, 1998): 2835–44. http://dx.doi.org/10.1128/mcb.18.5.2835.
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ABSTRACT The Epstein-Barr virus latent membrane protein 1 (LMP1) oncoprotein causes multiple cellular changes, including induction of epidermal growth factor receptor (EGFR) expression and activation of the NF-κB transcription factor. LMP1 and the cellular protein CD40, which also induces EGFR expression, interact with the tumor necrosis factor receptor-associated factor (TRAF) proteins. The LMP1 carboxy-terminal activation region 1 signaling domain interacts specifically with the TRAFs and is essential for EGFR induction through a mechanism independent of NF-κB alone. LMP1 and CD40 share a common TRAF binding motif, PXQXT. In this study, the PXQXT motifs in both LMP1 and CD40 were altered and mutant proteins were analyzed for induction of EGFR expression. Replacement of the T residue with A in CD40 completely blocked induction of the EGFR, while the same mutation in LMP1 did not affect EGFR induction. Replacement of both P and Q residues with A’s in LMP1 reduced EGFR induction by >75%, while deletion of PXQXT blocked EGFR induction. These results genetically link EGFR induction by LMP1 to the TRAF signaling pathway. Overexpression of TRAF2 potently activates NF-κB, although TRAF2 did not induce expression of the EGFR either alone or in combination with TRAF1 and TRAF3. In vivo analyses of the interaction of the TRAFs with LMP1 variants mutated in the PXQXT domain indicate that high-level induction of EGFR expression requires interaction with TRAF1, -2, and -3. However, exogenous expression of TRAF3 decreased EGFR induction mediated by either LMP1 or CD40. These data suggest that TRAF-mediated activation of EGFR expression requires assembly of a complex containing the appropriate stoichiometry of TRAF proteins clustered at the cell membrane with LMP1.
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Conti, Alfredo, M'Hammed Aguennouz, Domenico La Torre, Salvatore Cardali, Filippo Flavio Angileri, Catia Buemi, Chiara Tomasello, et al. "Expression of the tumor necrosis factor receptor—associated factors 1 and 2 and regulation of the nuclear factor—kB antiapoptotic activity in human gliomas." Journal of Neurosurgery 103, no. 5 (November 2005): 873–81. http://dx.doi.org/10.3171/jns.2005.103.5.0873.
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Object. Tumor necrosis factor receptor (TNFR)—associated factors (TRAFs) are a recently established group of proteins involved in the intracellular signaling of the TNFR superfamily members. The TRAFs have been implicated in promoting cell survival through the activation of transcription factor nuclear factor (NF)—κB. The authors investigated the expression of NF-κB, caspase 3, TRAF1, TRAF2, and TRAF-associated NF-κB activator/TRAF—interacting protein (TANK/I-TRAF), a regulator of TRAF activity, in human gliomas. Methods. Tumor samples were obtained in 27 adult patients harboring seven low-grade gliomas, nine anaplastic astrocytomas, and 11 glioblastomas multiforme. The NF-κB activation was analyzed using the electrophoresis mobility shift assay; TRAF1, TRAF2, TANK/I-TRAF, and caspase 3 expression were studied using Western blot analysis. Upregulated NF-κB DNA—binding activity, compared with that in normal brain tissue, was detected in all tumor samples (p = 0.002). The level of NF-κB activity showed some correlation with World Health Organization tumor grades (p = 0.01), even though variable activity levels were demonstrated in relation to tissue heterogeneity, which resulted in a substantial number of outliers in the quantitative analysis. Increased levels of TRAF1, TRAF2, and TANK/I-TRAF were expressed in astrocytomas compared with levels in normal brain tissue (p = 0.02, 0.006, and 0.01, respectively). Conclusions. Data in this study confirm the upregulation of NF-κB in gliomas and reveal a correlation between levels of this transcription factor and tumor grade. A constitutive expression of TRAF1, TRAF2, and TANK/I-TRAF in human gliomas was documented. These proteins are involved in the intracellular signal transduction of the TNFR superfamily and in the control of NF-κB expression and its antiapoptotic activity.
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Miyazaki, Ryo, Yoshiyuki Ohtsubo, Yuji Nagata, and Masataka Tsuda. "Characterization of the traD Operon of Naphthalene-Catabolic Plasmid NAH7: a Host-Range Modifier in Conjugative Transfer." Journal of Bacteriology 190, no. 19 (August 1, 2008): 6281–89. http://dx.doi.org/10.1128/jb.00709-08.
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ABSTRACT Pseudomonas putida G7 carries a naphthalene-catabolic and self-transmissible plasmid, NAH7, which belongs to the IncP-9 incompatibility group. Adjacent to the putative origin of conjugative transfer (oriT) of NAH7 are three genes, traD, traE, and traF, whose functions and roles in conjugation were previously unclear. These three genes were transcribed monocistronically and thus were designated the traD operon. Mutation of the three genes in the traD operon resulted in 10- to 105-fold decreases in the transfer frequencies of the plasmids from Pseudomonas to Pseudomonas and Escherichia coli and from E. coli to E. coli. On the other hand, the traD operon was essential for the transfer of NAH7 from E. coli to Pseudomonas strains. These results indicated that the traD operon is a host-range modifier in the conjugative transfer of NAH7. The TraD, TraE, and TraF proteins were localized in the cytoplasm, periplasm, and membrane, respectively, in strain G7 cells. Our use of a bacterial two-hybrid assay system showed that TraE interacted in vivo with other essential components for conjugative transfer, including TraB (coupling protein), TraC (relaxase), and MpfH (a channel subunit in the mating pair formation system).
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Bhat, Eijaz, Chang Kim, Sunghwan Kim, and Hyun Park. "In Vitro Inhibitory Mechanism Effect of TRAIP on the Function of TRAF2 Revealed by Characterization of Interaction Domains." International Journal of Molecular Sciences 19, no. 8 (August 20, 2018): 2457. http://dx.doi.org/10.3390/ijms19082457.
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TRAF-interacting protein (TRAIP), a negative regulator of TNF-induced-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, inhibits adaptor protein TRAF2 by direct interaction and is critical in apoptosis, cell proliferation, antiviral response, and embryonic development. Although the critical function of TRAIP in NF-κB signaling is well-known, the molecular inhibitory mechanism of TRAIP remains unclear. We found that the TRAIP coiled-coil domain altered its stoichiometry between dimer and trimer in a concentration-dependent manner. Additionally, the TRAIP RING domain induced even higher-ordered assembly, which was necessary for interacting with the TRAF-N domain of TRAF2 but not TRAF1. Characterization of the TRAF-N domains of TRAF1 and TRAF2, the tentative TRAIP-binding region of TRAFs, suggested the molecular basis of the inhibitory effect of TRAIP on TRAF2 in NF-κB signaling.
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Eliopoulos, Aristides G., Elyse R. Waites, Sarah M. S. Blake, Clare Davies, Paul Murray, and Lawrence S. Young. "TRAF1 Is a Critical Regulator of JNK Signaling by the TRAF-Binding Domain of the Epstein-Barr Virus-Encoded Latent Infection Membrane Protein 1 but Not CD40." Journal of Virology 77, no. 2 (January 15, 2003): 1316–28. http://dx.doi.org/10.1128/jvi.77.2.1316-1328.2003.
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ABSTRACT The oncogenic Epstein-Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) mimics a constitutive active tumor necrosis factor (TNF) family receptor in its ability to recruit TNF receptor-associated factors (TRAFs) and TNF receptor-associated death domain protein (TRADD) in a ligand-independent manner. As a result, LMP1 constitutively engages signaling pathways, such as the JNK and p38 mitogen-activated protein kinases (MAPK), the transcription factor NF-κB, and the JAK/STAT cascade, and these activities may explain many of its pleiotropic effects on cell phenotype, growth, and transformation. In this study we demonstrate the ability of the TRAF-binding domain of LMP1 to signal on the JNK/AP-1 axis in a cell type- dependent manner that critically involves TRAF1 and TRAF2. Thus, expression of this LMP1 domain in TRAF1-positive lymphoma cells promotes significant JNK activation, which is blocked by dominant-negative TRAF2 but not TRAF5. However, TRAF1 is absent in many established epithelial cell lines and primary nasopharyngeal carcinoma (NPC) biopsy specimens. In these cells, JNK activation by the TRAF-binding domain of LMP1 depends on the reconstitution of TRAF1 expression. The critical role of TRAF1 in the regulation of TRAF2-dependent JNK signaling is particular to the TRAF-binding domain of LMP1, since a homologous region in the cytoplasmic tail of CD40 or the TRADD-interacting domain of LMP1 signal on the JNK axis independently of TRAF1 status. These data further dissect the signaling components used by LMP1 and identify a novel role for TRAF1 as a modulator of oncogenic signals.
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Graham, John P., and Gail A. Bishop. "The role of the TRAF2/3 binding site in LMP1 and CD40 signaling (44.6)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 44.6. http://dx.doi.org/10.4049/jimmunol.182.supp.44.6.
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Abstract The Epstein-Barr virus protein, LMP1, is a mimic of the cellular receptor CD40. However, LMP1 signals to B lymphocytes in an amplified and sustained manner compared to CD40. LMP1 contributes to the development of B lymphoma in HIV patients or in immunosuppressed transplant recipients. LMP1 binds the signaling adaptor TRAF2 with lower affinity than CD40, and TRAF2 is needed for inducing CD40-mediated degradation of TRAFs 2 and 3. LMP1 doesn't induce TRAF degradation, and employs TRAF3 as a positive mediator of cell signaling, whereas CD40 signals are inhibited by TRAF3. We thus tested the hypothesis that relative affinity for TRAF2 and/or, distinct sequence differences in the TRAF2/3 binding sites (TBS) of CD40 vs. LMP1, controls the disparate ways in which CD40 and LMP1 use TRAFs 2 and 3, and their distinct signaling characteristics. We examined CD40 and LMP1 mutants in which the TBS sequences were swapped, testing TRAF binding and degradation, and induction of B cell activation. Results revealed that TRAF binding affinity and TBS sequence dictate some, but not all CD40 vs. LMP1 signaling properties. Examination of TRAF binding, degradation, cytokine production, IgM secretion, and the activation of c-Jun kinase and NF-kB revealed that some events are dictated by TBS sequences, others partially regulated, and still others appear independent of the TBS sequence. NIH grant CA099997
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Duckett, C. S., R. W. Gedrich, M. C. Gilfillan, and C. B. Thompson. "Induction of nuclear factor kappaB by the CD30 receptor is mediated by TRAF1 and TRAF2." Molecular and Cellular Biology 17, no. 3 (March 1997): 1535–42. http://dx.doi.org/10.1128/mcb.17.3.1535.
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CD30 is a lymphoid cell-specific surface receptor which was originally identified as an antigen expressed on Hodgkin's lymphoma cells. Activation of CD30 induces the nuclear factor kappaB (NF-kappaB) transcription factor. In this study, we define the domains in CD30 which are required for NF-kappaB activation. Two separate elements of the cytoplasmic domain which were capable of inducing NF-kappaB independently of one another were identified. The first domain (domain 1) mapped to a approximately 120-amino-acid sequence in the membrane-proximal region of the CD30 cytoplasmic tail, between residues 410 and 531. A second, more carboxy-terminal region (domain 2) was identified between residues 553 and 595. Domain 2 contains two 5- to 10-amino-acid elements which can mediate the binding of CD30 to members of the tumor necrosis factor receptor-associated factor (TRAF) family of signal transducing proteins. Coexpression of CD30 with TRAF1 or TRAF2 but not TRAF3 augmented NF-kappaB activation through domain 2 but not domain 1. NF-kappaB induction through domain 2 was inhibited by coexpression of either full-length TRAF3 or dominant negative forms of TRAF1 or TRAF2. In contrast, NF-kappaB induction by domain 1 was not affected by alterations in TRAF protein levels. Together, these data support a model in which CD30 can induce NF-kappaB by both TRAF-dependent and -independent mechanisms. TRAF-dependent induction of NF-kappaB appears to be regulated by the relative levels of individual TRAF proteins in the cell.
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Chen, Haiming, Richard A. Campbell, Daocheng Zhu, Sonia Guangxu Li, Christine Pan James, Janice Santos, Cathy S. Wang, Benjamin Bonavida, and James R. Berenson. "Inhibition of Multiple Myeloma Cell Proliferation and Increase of Apoptosis through Regulation of the NF-κB and JNK Pathways by Silencing TRAF6 C-Domain mRNA." Blood 104, no. 11 (November 16, 2004): 3355. http://dx.doi.org/10.1182/blood.v104.11.3355.3355.
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Abstract Several members of the tumor necrosis factor receptor-associated factor (TRAF) family, including TRAF2, TRAF5, and TRAF6 have been implicated in regulating signal transduction from various TRAF family members. However, the unique biological function of TRAF6 is largely determined by its TRAF-C domain, which does not interact with peptide motifs that are recognized by TRAF1, -2, -3 or -5. Based on TRAF6, CD40, and RANKL sequences and crystal structures, we targeted the TRAF6 C-domain residues from 420 to 440 because the TRAF6 interaction domain with CD40 or RANKL resides in residues 333 to 508. We found that silencing TRAF6 mRNA with the C-terminal domain siRNA significantly inhibited MM cell proliferation maximally at 72 hours whereas effects on inducing MM cell apoptosis were most prominent at 48 hours. The decrease in cell proliferation and increase in cell apoptosis occurred in a concentration (of siRNA)-dependent fashion. Furthermore, NF-κB mRNA expression and protein levels were also reduced using siRNA of the TRAF6 C-domain. We also examined the effect of TRAF6 siRNA on the JNK pathway since this signaling pathway is also associated with cell cycle effects in myeloma. We measured JUN kinase kinase (JNKK), which activates the MAP kinase homologues SAPK and JNK in response to IL-1 receptor stimulation. The results showed that the phosphorylation of JNKK is clearly reduced after knockdown of TRAF6 gene expression by siRNA. Furthermore, we examined c-Jun, a component of the transcription factor complex AP-1, which binds and activates transcription at TRE/AP-1 elements. The transcription activity of c-Jun is regulated by SAPK/JNK binding to c-Jun and phosphorylation of c-Jun at Ser63/73. We found that total endogenous c-Jun is reduced after silencing TRAF6 mRNA in the RPMI8226 MM cell line. In contrast, our data demonstrated that TRAF6 C-domain does not affect TRAF5 or TRAF2 gene expression. In addition, introduction of siRNA derived from the Zn-finger sequence into RPMI8226 MM cells failed to inhibit TRAF6 production. These studies suggest that the TRAF6 C-Domain may be an excellent target to block myeloma cell signaling important for the survival and proliferation of MM cells.
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Hostager, Bruce S., and Gail A. Bishop. "Cutting Edge: Contrasting Roles of TNF Receptor-Associated Factor 2 (TRAF2) and TRAF3 in CD40-Activated B Lymphocyte Differentiation." Journal of Immunology 162, no. 11 (June 1, 1999): 6307–11. http://dx.doi.org/10.4049/jimmunol.162.11.6307.
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Abstract In B lymphocytes, CD40 signals contribute to the activation of Ab secretion, isotype switching, T cell costimulation, and immunological memory. TRAF proteins appear to be important components of the CD40 signal transduction complex, but their roles in the activation of B cell effector functions are poorly understood. We examined the contributions of TNF receptor-associated factor 2 (TRAF2) and TRAF3 to CD40-activated differentiation in mouse B cells transfected with inducible TRAF and dominant-negative TRAF cDNAs. We find that binding of TRAF2 and TRAF3 to CD40 is not required for the induction of Ab secretion, but that both TRAF molecules can regulate the activation process. We demonstrate a negative regulatory role for TRAF3 and that this activity is dependent on the availability of an intact TRAF3-binding site in the cytoplasmic domain of CD40. In contrast, TRAF2 appears to play a positive role in B cell differentiation, and this activity is apparent even when its binding site on CD40 is disrupted.
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Arch, Robert H., and Craig B. Thompson. "4-1BB and Ox40 Are Members of a Tumor Necrosis Factor (TNF)-Nerve Growth Factor Receptor Subfamily That Bind TNF Receptor-Associated Factors and Activate Nuclear Factor κB." Molecular and Cellular Biology 18, no. 1 (January 1, 1998): 558–65. http://dx.doi.org/10.1128/mcb.18.1.558.
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ABSTRACT Members of the tumor necrosis factor (TNF)-nerve growth factor (NGF) receptor family have been shown to be important costimulatory molecules for cellular activation. 4-1BB and Ox40 are two recently described members of this protein family which are expressed primarily on activated T cells. To gain insight into the signaling pathways employed by these factors, yeast two-hybrid library screens were performed with the cytoplasmic domains of 4-1BB and Ox40 as baits. TNF receptor-associated factor 2 (TRAF2) was identified as an interacting protein in both screens. The ability of both 4-1BB and Ox40 to interact with TRAF2 was confirmed in mammalian cells by coimmunoprecipitation studies. When the binding of the receptors to other TRAF proteins was investigated, 4-1BB and Ox40 displayed distinct binding patterns. While 4-1BB bound TRAF2 and TRAF1, Ox40 interacted with TRAF3 and TRAF2. Using deletion and alanine scanning analysis, we defined the elements in the cytoplasmic domains of both receptors that mediate these interactions. The 4-1BB receptor was found to have two independent stretches of acidic residues that can mediate association of the TRAF molecules. In contrast, a single TRAF binding domain was identified in the cytoplasmic tail of Ox40. The cytoplasmic domains of both receptors were shown to activate nuclear factor κB in a TRAF-dependent manner. Taken together, our results indicate that 4-1BB and Ox40 bind TRAF proteins to initiate a signaling cascade leading to activation of nuclear factor κB.
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Gil, Jesús, Maria Angel García, Paulino Gomez-Puertas, Susana Guerra, Joaquín Rullas, Hiroyasu Nakano, José Alcamí, and Mariano Esteban. "TRAF Family Proteins Link PKR with NF-κB Activation." Molecular and Cellular Biology 24, no. 10 (May 15, 2004): 4502–12. http://dx.doi.org/10.1128/mcb.24.10.4502-4512.2004.
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ABSTRACT The double-stranded RNA (dsRNA)-dependent protein kinase PKR activates NF-κB via the IκB kinase (IKK) complex, but little is known about additional molecules that may be involved in this pathway. Analysis of the PKR sequence enabled us to identify two putative TRAF-interacting motifs. The viability of such an interaction was further suggested by computer modeling. Here, we present evidence of the colocalization and physical interaction between PKR and TRAF family proteins in vivo, as shown by immunoprecipitation and confocal microscopy experiments. This interaction is induced upon PKR dimerization. Most importantly, we show that the binding between PKR and TRAFs is functionally relevant, as observed by the absence of NF-κB activity upon PKR expression in cells genetically deficient in TRAF2 and TRAF5 or after expression of TRAF dominant negative molecules. On the basis of sequence information and mutational and computer docking analyses, we favored a TRAF-PKR interaction model in which the C-terminal domain of TRAF binds to a predicted TRAF interaction motif present in the PKR kinase domain. Altogether, our data suggest that TRAF family proteins are key components located downstream of PKR that have an important role in mediating activation of NF-κB by the dsRNA-dependent protein kinase.
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Arutyunov, Denis, Barbara Arenson, Jan Manchak, and Laura S. Frost. "F Plasmid TraF and TraH Are Components of an Outer Membrane Complex Involved in Conjugation." Journal of Bacteriology 192, no. 6 (January 15, 2010): 1730–34. http://dx.doi.org/10.1128/jb.00726-09.
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ABSTRACT F plasmid TraF and TraH are required for F pilus assembly and F plasmid transfer. Using flotation sucrose density gradients, we found that TraF and TraH (as well as TraU and TraW) localized to the outer membrane in the presence of the complete F transfer region, especially TraV, the putative anchor. Mutational analysis of TraH revealed two domains that are important for its function and possible interaction with TrbI, which in turn has a role in stabilizing TraH.
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Kashiwada, Masaki, Yumiko Shirakata, Jun-Ichiro Inoue, Hiroyasu Nakano, Kenji Okazaki, Ko Okumura, Tadashi Yamamoto, Hitoshi Nagaoka, and Toshitada Takemori. "Tumor Necrosis Factor Receptor–associated Factor 6 (TRAF6) Stimulates Extracellular Signal–regulated Kinase (ERK) Activity in CD40 Signaling Along a Ras-independent Pathway." Journal of Experimental Medicine 187, no. 2 (January 19, 1998): 237–44. http://dx.doi.org/10.1084/jem.187.2.237.
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CD40 activates nuclear factor kappa B (NFκB) and the mitogen-activated protein kinase (MAPK) subfamily, including extracellular signal–regulated kinase (ERK). The CD40 cytoplasmic tail interacts with tumor necrosis factor receptor–associated factor (TRAF)2, TRAF3, TRAF5, and TRAF6. These TRAF proteins, with the exception of TRAF3, are required for NFκB activation. Here we report that transient expression of TRAF6 stimulated both ERK and NFκB activity in the 293 cell line. Coexpression of the dominant-negative H-Ras did not affect TRAF6-mediated ERK activity, suggesting that TRAF6 may activate ERK along a Ras-independent pathway. The deletion mutant of TRAF6 lacking the NH2-terminal domain acted as a dominant-negative mutant to suppress ERK activation by full-length CD40 and suppress prominently ERK activation by a deletion mutant of CD40 only containing the binding site for TRAF6 in the cytoplasmic tail (CD40Δ246). Transient expression of the dominant-negative H-Ras significantly suppressed ERK activation by full-length CD40, but marginally suppressed ERK activation by CD40Δ246, compatible with the possibility that TRAF6 is a major transducer of ERK activation by CD40Δ246, whose activity is mediated by a Ras-independent pathway. These results suggest that CD40 activates ERK by both a Ras-dependent pathway and a Ras-independent pathway in which TRAF6 could be involved.
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Shirakata, Masaki, Ken-Ichi Imadome, Kenji Okazaki, and Kanji Hirai. "Activation of TRAF5 and TRAF6 Signal Cascades Negatively Regulates the Latent Replication Origin of Epstein-Barr Virus through p38 Mitogen-Activated Protein Kinase." Journal of Virology 75, no. 11 (June 1, 2001): 5059–68. http://dx.doi.org/10.1128/jvi.75.11.5059-5068.2001.
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ABSTRACT Latent Epstein-Barr virus (EBV) is maintained by the virus replication origin oriP that initiates DNA replication with the viral oriP-binding factor EBNA1. However, it is not known whether oriP's replicator activity is regulated by virus proteins or extracellular signals. By using a transient replication assay, we found that a low level of expression of viral signal transduction activator latent membrane protein 1 (LMP1) suppressed oriP activity. The binding site of the tumor necrosis factor receptor-associated factor (TRAF) of LMP1 was essential for this suppressive effect. Activation of the TRAF signal cascade by overexpression of TRAF5 and/or TRAF6 also suppressed oriPactivity. Conversely, blocking of TRAF signaling with dominant negative mutants of TRAF5 and TRAF6, as well as inhibition of a downstream signal mediator p38 MAPK, released the LMP1-inducedoriP suppression. Furthermore, activation of TRAF6 signal cascade by lipopolysaccharides (LPS) resulted in loss of EBV from Burkitt's lymphoma cell line Akata, and inhibition of p38 MAPK abolished the suppressive effect of LPS. These results suggested that the level of oriP activity is regulated by LMP1 and extracellular signals through TRAF5- and TRAF6-mediated signal cascades.
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Harris, Robin L., and Philip M. Silverman. "Tra Proteins Characteristic of F-Like Type IV Secretion Systems Constitute an Interaction Group by Yeast Two-Hybrid Analysis." Journal of Bacteriology 186, no. 16 (August 15, 2004): 5480–85. http://dx.doi.org/10.1128/jb.186.16.5480-5485.2004.
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ABSTRACT Using yeast two-hybrid screens, we have defined an interaction group of six Tra proteins encoded by the F plasmid and required by F+ cells to elaborate F pili. The six proteins are TraH, TraF, TraW, TraU, TrbI, and TrbB. Except for TrbI, these proteins were all identified as hallmarks of F-like type IV secretion systems (TFSSs), with no homologues among TFSS genes of P-type or I-type systems (T. Lawley, W. Klimke, M. Gubbins, and L. Frost, FEMS Microbiol. Lett. 224:1-15, 2003). Also with the exception of TrbI, which is an inner membrane protein, the remaining proteins are or are predicted to be periplasmic. TrbI consists of one membrane-spanning segment near its N terminus and an 88-residue, hydrophilic domain that extends into the periplasm. Hence, the proteins of this group probably form a periplasmic cluster in Escherichia coli. The interaction network identifies TraH as the most highly connected node, with two-hybrid links to TrbI, TraU, and TraF. As measured by transcriptional activation of lacZ, the TrbI-TraH interaction in Saccharomyces cerevisiae requires the TraH amino acid segment from residues 193 to 225. The TraU and TraF interactions are localized to C-terminal segments of TraH (amino acids 315 to 458 for TraF and amino acids 341 to 458 for TraU). The TrbI-TraH interaction with full-length (less the signal peptide) TraH is weak but increases 40-fold with N-terminal TraH deletions; the first 50 amino acids appear to be critical for inhibiting TrbI binding in yeast. Previous studies by others have shown that, with the exception of trbB mutations, which do not affect the elaboration or function of F pili under laboratory conditions, a mutation in any of the other genes in this interaction group alters the number or length distribution of F pili. We propose a model whereby one function of the TraH interaction group is to control F-pilus extension and retraction.
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Devergne, Odile, Ellen Cahir McFarland, George Mosialos, Kenneth M. Izumi, Carl F. Ware, and Elliott Kieff. "Role of the TRAF Binding Site and NF-κB Activation in Epstein-Barr Virus Latent Membrane Protein 1-Induced Cell Gene Expression." Journal of Virology 72, no. 10 (October 1, 1998): 7900–7908. http://dx.doi.org/10.1128/jvi.72.10.7900-7908.1998.
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ABSTRACT In this study, we investigated the induction of cellular gene expression by the Epstein-Barr Virus (EBV) latent membrane protein 1 (LMP1). Previously, LMP1 was shown to induce the expression of ICAM-1, LFA-3, CD40, and EBI3 in EBV-negative Burkitt lymphoma (BL) cells and of the epidermal growth factor receptor (EGF-R) in epithelial cells. We now show that LMP1 expression also increased Fas and tumor necrosis factor receptor-associated factor 1 (TRAF1) in BL cells. LMP1 mediates NF-κB activation via two independent domains located in its C-terminal cytoplasmic tail, a TRAF-interacting site that associates with TRAF1, -2, -3, and -5 through a PXQXT/S core motif and a TRADD-interacting site. In EBV-transformed B cells or transiently transfected BL cells, significant amounts of TRAF1, -2, -3, and -5 are associated with LMP1. In epithelial cells, very little TRAF1 is expressed, and only TRAF2, -3, and -5, are significantly complexed with LMP1. The importance of TRAF binding to the PXQXT/S motif in LMP1-mediated gene induction was studied by using an LMP1 mutant that contains alanine point mutations in this motif and fails to associate with TRAFs. This mutant, LMP1(P204A/Q206A), induced 60% of wild-type LMP1 NF-κB activation and had approximately 60% of wild-type LMP1 effect on Fas, ICAM-1, CD40, and LFA-3 induction. In contrast, LMP1(P204A/Q206A) was substantially more impaired in TRAF1, EBI3, and EGF-R induction. Thus, TRAF binding to the PXQXT/S motif has a nonessential role in up-regulating Fas, ICAM-1, CD40, and LFA-3 expression and a critical role in up-regulating TRAF1, EBI3, and EGF-R expression. Further, D1 LMP1, an LMP1 mutant that does not aggregate failed to induce TRAF1, EBI3, Fas, ICAM-1, CD40, and LFA-3 expression confirming the essential role for aggregation in LMP1 signaling. Overexpression of a dominant form of IκBα blocked LMP1-mediated TRAF1, EBI3, Fas, ICAM-1, CD40, and LFA-3 up-regulation, indicating that NF-κB is an important component of LMP1-mediated gene induction from both the TRAF- and TRADD-interacting sites.
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Gupta, Anish U., Shrey Gupta, Jenna McGowan, and Ritu Chakravarti. "In silico mapping of 14-3-3ζ and Human TRAF interaction." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 15.09. http://dx.doi.org/10.4049/jimmunol.206.supp.15.09.
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Abstract Recent advances show that the 14-3-3ζ protein participates in several immune regulations and is a unique regulator of IL-17A signal transduction. The IL-17A signal transduction triggers a 14-3-3ζ-TRAF5 dependent and a 14-3-3ζ-TRAF6 dependent intracellular pathway responsible for producing CXCL-1 and IL-6, respectively. Improved IL-17A signaling blockers are desirable in treating autoimmune diseases such as rheumatoid arthritis and lupus. Due to its unique role, 14-3-3ζ is an attractive target to regulate CXCL-1 and IL-6 levels. The aim of this study is to determine interaction sites between the 14-3-3ζ and TRAF (5 and 6) proteins using bioinformatic tools. We used 6EF5.pdb for 14-3-3ζ, 4GJH.pdb for TRAF5, and ILB6.pdb for TRAF6. Using ZDock, we examined the putative site of the 14-3-3ζ interactions on TRAF (5 and 6) with restrictions and without restrictions. The mapped interacting residues were mutated, and an effect on the interaction with 14-3-3ζ was observed. To further evaluate the interaction quality, we utilized Prodigy to measure the binding energy for several possible structures and narrow down the selected interaction sites further. Results indicate that site 479–485 is the putative target site of the 14-3-3ζ-TRAF5 complex with a ΔG of −10.1 kcal/mol and a Kd of 4.00×10−8. By comparison, residues 483–488 on TRAF6 interact with 14-3-3ζ with a ΔG of −19.1 kcal/mol and a Kd of 9.50×10−15. Our results demonstrate the putative binding sites between the 14-3-3ζ and TRAF (5 and 6) proteins. However, our study has the limitation of using the available but incomplete TRAF structures; therefore, lab studies should be used to confirm these results. Our results provide a rationale to investigate the 14-3-3ζ and TRAF proteins further.
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Li, Gongbo, Justin C. Boucher, Hiroshi Kotani, Yongliang Zhang, Bishwas Shrestha, Bin Yu, and Marco L. Davila. "Selective TRAF over-expression enhances CD19-targeted 41BB CAR T function by increasing NF-κB." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 179.10. http://dx.doi.org/10.4049/jimmunol.200.supp.179.10.
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Abstract The prototypical second-generation CD19-targeted CAR (chimeric antigen receptor) features a costimulatory domain, either CD28 or 41BB, with both designs achieving comparable clinical outcomes against B cell malignancies. However, clinical application of CAR T cells has outpaced the understanding of their functions in vivo. We evaluated fully murine CD19-targeted CAR T cells containing CD28 or 41BB endodomain in an immune competent B-ALL (B cell acute lymphoblastic leukemia) mouse model. Mouse 41BB CAR T cells imparted inferior survival to mouse CD28 CAR T cells at a stress-test dose. Replacing mouse 41BB endodomain with human 41BB sequence significantly increased NF-κB signaling in 41BB CAR T cells and enhanced survival and persistence to match the mouse CD28 CAR T cells. TRAF binding and its subsequent NF-κB signaling are more important to 41BB than CD28 CAR T functions as evidenced by TRAF1 deficient 41BB but not CD28 CAR T cells showing inferior in vivo B cell killing and CAR T persistence to wild type CAR T cells. Also, 41BB CAR T cells with impaired TRAF binding showed remarkably decreased NF-κB signaling, viability and proliferation in vitro. Over-expressing TRAF2 or TRAF3 but not TRAF1 significantly enhanced CD19 targeted 41BB CAR T functions, such as cytotoxicity, viability and proliferation. Our study demonstrates how co-stimulatory domains impact CAR T functions and selective TRAF over-expression could be a new strategy to improve current CAR T therapy.
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Kuhné, Michelle R., Michael Robbins, John E. Hambor, Matthew F. Mackey, Yoko Kosaka, Toshihide Nishimura, Jason P. Gigley, Randolph J. Noelle, and David M. Calderhead. "Assembly and Regulation of the CD40 Receptor Complex in Human B Cells." Journal of Experimental Medicine 186, no. 2 (July 21, 1997): 337–42. http://dx.doi.org/10.1084/jem.186.2.337.
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CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily. Studies with human B cells show that the binding of CD154 (gp39, CD40L) to CD40 recruits TNF receptor– associated factor 2 (TRAF2) and TRAF3 to the receptor complex, induces the downregulation of the nonreceptor-associated TRAFs in the cell and induces an increased expression of Fas on the cell surface. Combined signaling through the interluekin 4 receptor and CD40 induces an increased expression of Fas with a commensurate increase in the level of TRAF2, but not TRAF3, that is recruited to the receptor complex. In contrast, engagement of the membrane immunoglobulin and CD40 limits Fas upregulation and reduces the recruitment of TRAF2, relative to TRAF3, to the CD40 receptor complex. These studies show that the TRAF composition of the CD40 receptor complex can be altered by signals that influence B cell differentiation.
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Hsu, Ping-Ning, Hsiu-Jung Liao, and Hwei-Fang Tsai. "TRAF-6 dependent signaling pathway is essential for TNF-related apoptosis-inducing ligand (TRAIL) induces osteoclast differentiation (54.21)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 54.21. http://dx.doi.org/10.4049/jimmunol.188.supp.54.21.
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Abstract Human osteoclast formation from mononuclear phagocyte precursors involves interactions between tumor necrosis factor (TNF) ligand superfamily members and their receptors. Recent evidence indicates that in addition to triggering apoptosis, the TNF-related apoptosis-inducing ligand (TRAIL) induces osteoclast differentiation. To understand TRAIL-mediated signal transduction mechanism in osteoclastogenesis, we demonstrated that TRAIL induces osteoclast differentiation via a Tumor necrosis factor receptor-associated factor 6 (TRAF-6)-dependent signaling pathway. TRAIL-induced osteoclast differentiation was significantly inhibited by treatment with TRAF-6 siRNA and TRAF6 decoy peptides in both human monocytes and murine RAW264.7 macrophage cell lines, as evaluated in terms of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and bone resorption activity. Moreover, TRAIL-induced osteoclast differentiation was also abolished in TRAF6 knockout bone marrow macrophages. In addition to induction of NFATc1, treatment of TRAIL also induced ubiquitination of TRAF6 in osteoclast differentiation. Thus, our data demonstrate that TRAIL induces osteoclastic differentiation via a TRAF-6 dependent signaling pathway. This study suggests TRAF6-dependent signaling may be a central pathway in osteoclast differentiation, and that TNF superfamily molecules other than RANKL may modify RANK signaling by interaction with TRAF6-associated signaling.
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Ramalingam, Preetha, Wei-Sing Chu, Raymond Tubbs, Lisa Rybicki, James Pettay, and Eric D. Hsi. "Latent Membrane Protein 1, Tumor Necrosis Factor Receptor–Associated Factor (TRAF) 1, TRAF-2, TRAF-3, and Nuclear Factor Kappa B Expression in Posttransplantation Lymphoproliferative Disorders." Archives of Pathology & Laboratory Medicine 127, no. 10 (October 1, 2003): 1335–39. http://dx.doi.org/10.5858/2003-127-1335-lmptnf.
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Abstract Context.—Most posttransplantation lymphoproliferative disorders (PTLDs) are associated with Epstein-Barr virus (EBV) infection. The EBV latent membrane protein 1 (LMP-1) is important in the transformation of B lymphocytes through its interaction with intracellular tumor necrosis factor receptor–associated factors (TRAFs) that, in turn, can activate transcription factors such as nuclear factor kappa B (NFκB) and Jun-N-kinase. Of the 6 members of the TRAF family, TRAF-1, TRAF-2, and TRAF-3 are most commonly associated with LMP-1. Recently, it has been suggested that LMP-1–induced TRAF activation is important in the pathogenesis of PTLDs. Objective.—To characterize the expression patterns of these proteins in PTLDs, we studied a series of well-characterized cases for expression of LMP-1, TRAF-1, TRAF-2, TRAF-3, and NFκB by immunohistochemical analysis. Methods.—A total of 27 specimens from 25 patients were analyzed for LMP-1, TRAF-1, TRAF-2, TRAF-3, and NFκB (active form) by immunohistochemical analysis. Expression of EBV-encoded RNA (EBER) was evaluated by in situ hybridization. Correlation between the expression of the different markers was performed using the Mantel-Haenszel χ2 test. Cox proportional hazards analysis and Kaplan-Meier analysis with log-rank testing were used to analyze antigen expression and clinical outcome. Results.—Ninety-six percent of PTLDs expressed NFκB, 74% to 84% expressed TRAFs, 78% expressed EBER, and 77% expressed LMP-1. TRAF-1, TRAF-2, and TRAF-3 expression did not correlate with either EBER or LMP-1 expression. TRAF-2, but not TRAF-1 or TRAF-3, expression correlated with NFκB expression (P = .02). Conclusions.—These results suggest that TRAF molecules and active NFκB are expressed in PTLDs regardless of EBV positivity. Given the association of TRAF-2 and active NFκB expression, TRAF-2 may play an important role in regulating this transcription factor in PTLD.
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Shen, Jun, Yuqi Qiao, Zhihua Ran, and Tianrong Wang. "Different Activation of TRAF4 and TRAF6 in Inflammatory Bowel Disease." Mediators of Inflammation 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/647936.
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In recent years, interests combining the exploration of tumor necrosis factor receptor-associated factor 4 (TRAF4) and TRAF6 in immune cells and transgenic mice are emerging. Although it has been found that TRAF4 and TRAF6 share the same TRAF binding sites, comprehensive study of TRAF4 and TRAF6 in inflammatory bowel disease (IBD) is still lacking. This paper shows similar and different expression patterns of TRAF4 and TRAF6 in patients with IBD. The results indicate that TRAF4 and TRAF6 are overexpressed in IBD. TRAF4 and TRAF6 play different roles in the pathogenesis of IBD. Moreover, TRAF4 may be an indicator of endoscopic disease activity of UC and TRAF6 preactivation can be detected in noninflamed colonic segments.
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Buchta, Claire, and Gail Bishop. "TRAF5 negatively regulates Toll-like receptor signaling (P1226)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 138.11. http://dx.doi.org/10.4049/jimmunol.190.supp.138.11.
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Abstract Dysregulation in Toll-like receptor (TLR) signaling has been implicated in various inflammatory and autoimmune disorders. The cytoplasmic adaptor proteins TNF receptor associated factor (TRAF)3 and TRAF6 are known to mediate TLR signaling. Data from our lab suggest for the first time that another family member, TRAF5, is a negative regulator of TLR signaling. B lymphocytes, macrophages, and dendritic cells from TRAF5-/- mice have enhanced early signaling pathways including increased phosphorylation of the kinases ERK1/2, JNK, and Akt . They also produce more cytokines after TLR ligation. Consistent with these results, overexpression of TRAF5 in B cells inhibits TLR-induced cytokine production. Pursuing the mechanism of TRAF5-mediated regulation, we discovered that TRAF5 negatively regulates the transcription and protein levels of TRAF6. Additionally, TRAF5 associates in a complex with TRAF3, TRAF6, and the TLR adaptor protein MyD88 after TLR stimulation in B cells. Results suggest multiple mechanisms by which TRAF5 negatively regulates TLR signaling. TRAF5 deficiency has been reported to accelerate atherogenesis in mice. Elucidating the role of TRAF5 in TLR signaling may thus provide a new target for therapies against a variety of inflammatory conditions.
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Leleu, Xavier, Lian Xu, Zachary R. Hunter, Sophia Adamia, Evdoxia Hatjiharissi, Anne-Sophie Moreau, Aldo Roccaro, et al. "Biological Sequelae of TRAF2 Downregulation in Waldenstrom Macroglobulinemia Cells." Blood 110, no. 11 (November 16, 2007): 3526. http://dx.doi.org/10.1182/blood.v110.11.3526.3526.
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Abstract Background. Several TNF family members (CD40L and BAFF/BLYS) have been implicated in Waldenstrom’s Macroglobulinemia (WM) cell growth and survival. More recently, abnormalities in the APRIL-TACI pathway have been demonstrated by us in WM cells (Hunter, ASH2006, #228). TRAFs (TNFR-associated factor) are a family of adaptor proteins that mediate signal transduction from multiple members of the TNF receptor superfamily. In particular, TRAFs facilitate pro-apoptotic signaling from the TACI receptor, and TRAF2 is of importance among the TRAF adapter proteins since this protein is required for TNF-alpha-mediated activation of SAPK/JNK MAPK known to be involved in drug-induced death of tumor B cells. We therefore examined the role of TRAF2 in WM growth and survival. Method. We investigated TRAF2, 3 and 5 gene expression in WM patient bone marrow (BM) CD19+ cells and cell lines (BCWM.1, WSU-WM) and compared their expression to BM CD19+ cells from healthy donors. Expression of human TRAF transcripts were determined using real time quantitative RT-PCR (qPCR) based on TaqMan fluorescence methodology. To evaluate the role of TRAF2, a knockdown model was prepared in BL2126 B-cells and BCWM.1 WM cells using electroporation, with resulted ≥50% knockdown efficiency using RT-PCR and immunoblotting. Results. We found that TRAF3 and 5 gene expression was higher in WM versus healthy donors, while TRAF2 expression was lower in 8/13 (60%) patients, using qPCR. TRAFs gene expression did not correlate with tumor burden or WM prognostic markers. We next sought to understand the biological sequelae of TRAF2 deficiency in BL2126 and BCWM.1 cells and found that TRAF2 knockdown induced increased survival at 72 hours in both cell lines. We next studied sequence analysis of 20 WM patients CD19+ BM cells to determine whether there was a TRAF2 genomic alteration, and found heterozygous early termination mutation in exon 5 in 1 (5%) patient. Conclusion. Our data demonstrate that TRAF2 is a commonly dysregulated TNF family adapter protein in patients with WM, with important consequences in WM cell growth and survival.
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Guo, Feng, Zi-Xing Chen, Aining Sun, Peng Zhou, and Wenjuan Wang. "Differential Effects of TRAFs in the Activation of NF-KappB in Hodgkin’s Lymphoma Cells." Blood 112, no. 11 (November 16, 2008): 1458. http://dx.doi.org/10.1182/blood.v112.11.1458.1458.
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Abstract CD30, a member of the TNF receptor (TNFR) superfamily, is a lymphocyte-specific receptor that is originally recognized as a surface molecule overexpressed on Hodgkin’s lymphoma cells. Engagement of CD30 with its ligand CD30L activates the nuclear factor kB (NF-kB), which are mediated by interactions with TNFR-associated factor (TRAFs), and supports proliferation of Hodgkin’s cells. However, the role of individual TRAFs in the CD30 signaling pathway in Hodgkin’s cells has not been fully addressed yet. In this study, we found that except TRAF3, all other TRAFs were expressed consistently in B cell-derived Hodgkin’s cell lines (L428 and KM-H2) either in mRNA or protein level. In L428 but not KM-H2 cells, the classical (p50-RelA) and alternative (p52-RelB) NF-kB activity were constitutively activated measured by Western Blotting and EMSA. To better understand the CD30 signaling properties in Hodgkin’s lymphoma cells, we silenced the expression of TRAFs individually by means of RNAi. Successful downregulation of TRAF1 protein expression led to the apoptosis of L428 cells, which was companied by the reduction of both classical and alternative NF-kB activity. Furthermore, the expression of targeting genes of NF-kB, such as A20, c-Flip, ICAM-1, and Cyclin D1 was also decreased. Using siRNA targeting TRAF2 expression, the classical NF-kB activity was reduced while the alternative NF-kB activity moderately induced especially upon CD30L treatment, which was companied by the induction of p100 processing and RelB nuclear localization. The survival rate was decreased when TRAF2 was knockdown. TRAF5 knockdown manifested similar results as that of TRAF2. These observations were only took place in L428 cells but not KM-H2 cells. In addition, the phosphorylation of the extracellular signal-regulated kinases (ERK) 1 and 2, and subsequent activation of JunB in Hodgkin’s cells were staying unchanged in individual TRAFs knockdown experiment. Taken together, the study here further investigates the features of CD30-TRAFs-NF-kB signaling pathway in Hodgkin’s lymphoma cells. At least TRAF1, 2, and 5 are involved in CD30 signaling pathway and protecting Hodgkin’s lymphoma cells from undergoing apoptosis. The interaction between TRAFs is necessary to facilitate the signaling and proper activation of classical NF-kB, which is responsible for the antiapoptotic effect of Hodgkin’s cells. Among TRAF1, 2, and 5, the redundant function is unlikely. Furthermore, the sequential activation of ERK and JunB is unlikely dependent on TRAFs-NF-kB pathway in Hodgkin’s lymphoma cells. Thus, these data reveal that the classical NF-kB activity downstream of CD30 signaling is TRAFs-dependent in Hodgkin’s lymphoma cells, which is regulated by the relative level of individual TRAF in a cell-specific manner.
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Izumi, Kenneth M., Ellen Cahir McFarland, Elisabeth A. Riley, Danielle Rizzo, Yuzhi Chen, and Elliott Kieff. "The Residues between the Two Transformation Effector Sites of Epstein-Barr Virus Latent Membrane Protein 1 Are Not Critical for B-Lymphocyte Growth Transformation." Journal of Virology 73, no. 12 (December 1, 1999): 9908–16. http://dx.doi.org/10.1128/jvi.73.12.9908-9916.1999.
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ABSTRACT Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is essential for EBV-mediated transformation of primary B lymphocytes. LMP1 spontaneously aggregates in the plasma membrane and enables two transformation effector sites (TES1 and TES2) within the 200-amino-acid cytoplasmic carboxyl terminus to constitutively engage the tumor necrosis factor receptor (TNFR)-associated factors TRAF1, TRAF2, TRAF3, and TRAF5 and the TNFR-associated death domain proteins TRADD and RIP, thereby activating NF-κB and c-Jun N-terminal kinase (JNK). To investigate the importance of the 60% of the LMP1 carboxyl terminus that lies between the TES1-TRAF and TES2-TRADD and -RIP binding sites, an EBV recombinant was made that contains a specific deletion of LMP1 codons 232 to 351. Surprisingly, the deletion mutant was similar to wild-type (wt) LMP1 EBV recombinants in its efficiency in transforming primary B lymphocytes into lymphoblastoid cell lines (LCLs). Mutant and wt EBV-transformed LCLs were similarly efficient in long-term outgrowth and in regrowth after endpoint dilution. Mutant and wt LMP1 proteins were also similar in their constitutive association with TRAF1, TRAF2, TRAF3, TRADD, and RIP. Mutant and wt EBV-transformed LCLs were similar in steady-state levels of Bcl2, JNK, and activated JNK proteins. The wt phenotype of recombinants with LMP1 codons 232 to 351 deleted further demarcates TES1 and TES2, underscores their central importance in B-lymphocyte growth transformation, and provides a new perspective on LMP1 sequence variation between TES1 and TES2.
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Li, Mingjie, Eric Sanchez, Cathy Wang, Megan Schultz, Jessica Wang, Emily Wong, Zhi-Wei Li, et al. "Blockage of TRAF6 by Dominant Negative Peptides to Inhibit Multiple Myeloma (MM) Cell Proliferation and Osteoclast Formation through NF-κB, JNK and AKT Signal Transduction Pathways." Blood 116, no. 21 (November 19, 2010): 4068. http://dx.doi.org/10.1182/blood.v116.21.4068.4068.
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Abstract Abstract 4068 Several members of the tumor necrosis factor receptor-associated factor (TRAF) family, including TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6 have been implicated in regulating signal transduction from various TRAF family members. However, the unique biological function of TRAF6 is largely determined by its TRAF-C domain, which does not interact with peptide motifs that are recognized by TRAF1, -2, -3 or -5. We have reported inhibition of MM cell proliferation and increase of apoptosis through regulation of the NF-κB and JNK pathways through silencing TRAF6 C-domain mRNA and the dominant negative peptide expression vector (Chen H. et al, Oncogene, 2006; Li M. et al, Blood 2009). TRAF6 have been recently found as a ligase for Akt ubiquitination (Yang WL et al, Science, 2009). Akt signaling plays a central role in many biological functions, such as cell proliferation and apoptosis. In this study, we first investigated whether TRAF6 is over-expressed in MM tumor cells. Twelve MM fresh bone marrow (BM) aspirates derived from MM patients were assessed using Western blot analysis and immunohistochemical staining with anti-TRAF6 antibody. We found that TRAF6 protein was highly expressed in tumor cells from MM patients compared to normal human BM samples. Based on TRAF6, CD40, and RANKL sequences and crystal structures, we targeted the TRAF6 C-domain binding residues. We found that TRAF6 dominant negative binding peptide (TRAF6dn) significantly inhibited MM cell proliferation maximally at 72 hours using the MTS cell proliferation assay whereas effects on inducing MM cell apoptosis were most prominent at 48 hours as assessed with Annexin V staining with flow cytometric analysis. The decrease in cell proliferation and increase in cell apoptosis occurred in a concentration peptide-dependent fashion. Furthermore, phosphorylation of both AKT and NF-κB were also reduced using our human TRAF6dn or decoy peptides. We also examined the effect of the TRAF6dn peptide on the JNK pathway since this signaling pathway is also associated with cell cycle effects in MM. We measured JUN kinase kinase (JNKK), which activates the MAP kinase homologues SAPK and JNK in response to IL-1 receptor stimulation. The results showed that the phosphorylation of JNKK is markedly reduced after treatment with the TRAF6dn peptide. Furthermore, we examined c-Jun, a component of the transcription factor complex AP-1, which binds and activates transcription at TRE/AP-1 elements. We evaluated the effect of TRAF6dn peptide on osteoclast formation using cells from human monocytes isolated by anti-CD14 micro-bead affinity column from MM patients' BM or peripheral blood mononuclear cells. The monocytes were cultured on slide-culture dishes (2 × 105 cells/well).We found TRAF6dn markedly inhibited osteoclast cell formation from monocytes induced with RANKL and mCSF in a concentration- dependent fashion compared with a control group using tartrate resistant acid phosphatase staining. We further assessed whether TRAF6dn can reduce bone resorption using a dentin bone resorption assay. BM-derived monocytes were isolated as above and were cultured on dentin bone slides (4 × 105 cells/slide). The cells treated with a TRAF6dn peptide or the control peptide, were incubated with 50ng/ml RANKL and 10ng/ml MCSF. All cells were cultured for 21 days. It was found that TRAF6dn significantly inhibited lacunar resorption in a concentration-dependent fashion. These studies suggest that TRAF6 is over-expressed in MM and our TRAF6dn peptide inhibits many signaling pathways critical to the growth of MM and formation of osteoclasts resulting in marked anti-MM effects and reduction in osteoclast formation resulting in marked inhibition of bone resorption. Thus, this novel approach may offer a new therapeutic approach to both treat multiple myeloma and reduce the clinical consequences resulting from enhanced bone loss that commonly occur in these patients. Disclosures: No relevant conflicts of interest to declare.
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Lee, Heuiran, Joong-Kook Choi, Mengtao Li, Ken Kaye, Elliott Kieff, and Jae U. Jung. "Role of Cellular Tumor Necrosis Factor Receptor-Associated Factors in NF-κB Activation and Lymphocyte Transformation by Herpesvirus Saimiri STP." Journal of Virology 73, no. 5 (May 1, 1999): 3913–19. http://dx.doi.org/10.1128/jvi.73.5.3913-3919.1999.
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ABSTRACT The STP oncoproteins of the herpesvirus saimiri (HVS) subgroup A strain 11 and subgroup C strain 488 are now found to be stably associated with tumor necrosis factor receptor-associated factor (TRAF) 1, 2, or 3. Mutational analyses identified residues of PXQXT/S in STP-A11 as critical for TRAF association. In addition, a somewhat divergent region of STP-C488 is critical for TRAF association. Mutational analysis also revealed that STP-C488 induced NF-κB activation that was correlated with its ability to associate with TRAFs. The HVS STP-C488 P10→R mutant was deficient in human T-lymphocyte transformation to interleukin-2-independent growth but showed wild-type phenotype for marmoset T-lymphocyte transformation in vitro and in vivo. The STP-C488 P10→R mutant was also defective in Rat-1 fibroblast transformation, and fibroblast cell transformation was blocked by a TRAF2 dominant-negative mutant. These data implicate TRAFs in STP-C488-mediated transformation of human lymphocytes and rodent fibroblasts. Other factors are implicated in immortalization of common marmoset T lymphocytes and may also be critical in the transformation of human lymphocytes and rodent fibroblasts.
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Chung, Jee Y., Young Chul Park, Hong Ye, and Hao Wu. "All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction." Journal of Cell Science 115, no. 4 (February 15, 2002): 679–88. http://dx.doi.org/10.1242/jcs.115.4.679.
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The tumor necrosis factor (TNF) receptor associated factors (TRAFs) have emerged as the major signal transducers for the TNF receptor superfamily and the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily. TRAFs collectively play important functions in both adaptive and innate immunity. Recent functional and structural studies have revealed the individuality of each of the mammalian TRAFs and advanced our understanding of the underlying molecular mechanisms. Here, we examine this functional divergence among TRAFs from a perspective of both upstream and downstream TRAF signal transduction pathways and of signaling-dependent regulation of TRAF trafficking. We raise additional questions and propose hypotheses regarding the molecular basis of TRAF signaling specificity.
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Kim, Chang Min, and Hyun Ho Park. "Comparison of Target Recognition by TRAF1 and TRAF2." International Journal of Molecular Sciences 21, no. 8 (April 21, 2020): 2895. http://dx.doi.org/10.3390/ijms21082895.
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Although TRAF1 and TRAF2 share common receptors and have extremely conserved amino acid residues, recent studies have shown that key differences in receptor binding preferences with different affinities exist, which might be important for their different functions in TRAF-mediated signal transduction. To better understand TRAF1 and TRAF2 signaling, we analyzed and compared their receptor binding-affinities. Our study revealed that TRADD, TANK, and caspase-2 bind to both TRAF1 and TRAF2 with different affinities in vitro. Sequence and structural analyses revealed that S454 on TRAF2 (corresponding to A369 of TRAF1) is critical for the binding of TRADD, and F347 on TRAF1 (corresponding to L432 of TRAF2) is a critical determinant for high affinity binding of TANK and caspase-2.
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Xiao, Ning, Hui Li, Jian Luo, Rui Wang, Haiquan Chen, Jiquan Chen, and Ping Wang. "Ubiquitin-specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFα-induced cancer cell migration." Biochemical Journal 441, no. 3 (January 16, 2012): 979–87. http://dx.doi.org/10.1042/bj20111358.
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TRAF [TNF (tumour necrosis factor)-receptor-associated factor] 2 and 6 are essential adaptor proteins for the NF-κB (nuclear factor κB) signalling pathway, which play important roles in inflammation and immune response. Polyubiquitination of TRAF2 and TRAF6 is critical to their activities and functions in TNFα- and IL (interleukin)-1β-induced NF-κB activation. However, the regulation of TRAF2 and TRAF6 by deubiquitination remains incompletely understood. In the present study, we identified USP (ubiquitin-specific protease) 4 as a novel deubiquitinase targeting TRAF2 and TRAF6 for deubiquitination. We found that USP4 specifically interacts with TRAF2 and TRAF6, but not TRAF3. Moreover, USP4 associates with TRAF6 both in vitro and in vivo, independent of its deubiquitinase activity. The USP domain is responsible for USP4 to interact with TRAF6. Ectopic expression of USP4 inhibits the TRAF2- and TRAF6-stimulated NF-κB reporter gene and negatively regulates the TNFα-induced IκBα (inhibitor of NF-κBα) degradation and NF-κB activation. Knockdown of USP4 significantly increased TNFα-induced cytokine expression. Furthermore, we found that USP4 deubiquitinates both TRAF2 and TRAF6 in vivo and in vitro in a deubiquitinase activity-dependent manner. Importantly, the results of the present study showed that USP4 is a negative regulator of TNFα- and IL-1β-induced cancer cell migration. Taken together, the present study provides a novel insight into the regulation of the NF-κB signalling pathway and uncovers a previously unknown function of USP4 in cancer.
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Grahn, A. Marika, Jana Haase, Dennis H. Bamford, and Erich Lanka. "Components of the RP4 Conjugative Transfer Apparatus Form an Envelope Structure Bridging Inner and Outer Membranes of Donor Cells: Implications for Related Macromolecule Transport Systems." Journal of Bacteriology 182, no. 6 (March 15, 2000): 1564–74. http://dx.doi.org/10.1128/jb.182.6.1564-1574.2000.
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ABSTRACT During bacterial conjugation, the single-stranded DNA molecule is transferred through the cell envelopes of the donor and the recipient cell. A membrane-spanning transfer apparatus encoded by conjugative plasmids has been proposed to facilitate protein and DNA transport. For the IncPα plasmid RP4, a thorough sequence analysis of the gene products of the transfer regions Tra1 and Tra2 revealed typical features of mainly inner membrane proteins. We localized essential RP4 transfer functions to Escherichia coli cell fractions by immunological detection with specific polyclonal antisera. Each of the gene products of the RP4 mating pair formation (Mpf) system, specified by the Tra2 core region and by traF of the Tra1 region, was found in the outer membrane fraction with one exception, the TrbB protein, which behaved like a soluble protein. The membrane preparation from Mpf-containing cells had an additional membrane fraction whose density was intermediate between those of the cytoplasmic and outer membranes, suggesting the presence of attachment zones between the twoE. coli membranes. The Tra1 region is known to encode the components of the RP4 relaxosome. Several gene products of this transfer region, including the relaxase TraI, were detected in the soluble fraction, but also in the inner membrane fraction. This indicates that the nucleoprotein complex is associated with and/or assembled facing the cytoplasmic site of the E. coli cell envelope. The Tra1 protein TraG was predominantly localized to the cytoplasmic membrane, supporting its potential role as an interface between the RP4 Mpf system and the relaxosome.
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Missiou, Anna, Natascha Köstlin, Christian Münkel, Dietmar Pfeifer, Katja Zirlik, Christoph Bode, Peter Libby, and Andreas Zirlik. "TRAF-1 Deficient Mice Show Impaired Monocyte Recruitment and Decreased Atherogenesis." Blood 112, no. 11 (November 16, 2008): 696. http://dx.doi.org/10.1182/blood.v112.11.696.696.
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Abstract Members of the tumor necrosis factor (TNF) interleukin/toll-like receptor superfamily such as CD40L, TNFa, and IL-1b potently promote atherogenesis in mice and likely also in humans. TNF receptor associated factors (TRAFs) are cytoplasmic adaptor proteins for this group of cytokines. We recently reported over-expression of TRAFs in murine and human atheromata and demonstrated dependency of classic inflammatory functions on TRAFs in endothelial cells and macrophages. Here we test the hypothesis that TRAF-1 modulates atherogenesis in vivo. TRAF-1--/LDLR--mice fed a high cholesterol diet for 18 weeks developed significantly smaller atherosclerotic lesions compared with LDLR--controls. Intimal lesion size decreased by up to 56±6% and 33±5% in sections of the aortic arch and aortic root, respectively (n>10 per group, P<0.01 each). Plaques of TRAF-1-deficient animals contained up to 46±9% and 55±4% fewer macrophages while smooth muscle cell content increased by up to 32±6 and 36±7%, characteristics associated with non disrupted plaques in humans. Lipid content, collagen content, and lymphocyte content remained unchanged. In vitro, gene expression profiling revealed reduced expression of adhesion molecules (VCAM-1, ICAM-1), chemokines (CCL2, CXCL2), and growth factors (M-CSF) in TRAF-1-deficient endothelial cells as well as of integrins (CD29, CD11b) and chemokines/chemokine receptors (CXCL2, CCR1) in TRAF-1-deficient macrophages, verified by siRNA studies in human cells. Finally, both deficiency of TRAF-1 in endothelial cells and neutrophils/monocytes reduced adhesion of inflammatory cells to the endothelium in static and dynamic adhesion assays. We present the novel finding that TRAF 1 deficiency attenuates atherogenesis in mice, an effect most likely mediated by impaired monocyte recruitment to the vessel wall. These data identify TRAF-1 as potential treatment target for chronic inflammatory diseases such as atherosclerosis.
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Foight, Glenna Wink, and Amy E. Keating. "Comparison of the peptide binding preferences of three closely related TRAF paralogs: TRAF2, TRAF3, and TRAF5." Protein Science 25, no. 7 (February 3, 2016): 1273–89. http://dx.doi.org/10.1002/pro.2881.
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Pham, Lan V., Yen-Chiu Lin-Lee, Hai-Jun Zhou, Archito T. Tamayo, Linda C. Yoshimura, and Richard J. Ford. "TRAF6 and C-myb Show Novel Functions in the Nucleus of Lymphoma B Cells." Blood 108, no. 11 (November 1, 2006): 2376. http://dx.doi.org/10.1182/blood.v108.11.2376.2376.
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Abstract The tumor necrosis factor (TNF) family (TNF-R; CD40; BAFF-R) plays a key role in neoplastic as well as normal B cell growth and survival mechanisms. TNF receptor-associated factor-6 (TRAF-6) is an adapter molecule that regulates several important signaling pathways critical for cell growth and cell survival. It is a member of seven closely related TRAF proteins that serve as signaling molecules, coupling to TNF-receptor superfamily to intracellular signaling, particularly in the CD40 Signalosome. TRAF6 has shown to be over-expressed and play an important role in cell growth and cell survival through the activation of the key transcription factor NF-kB in aggressive non-Hodgkin’s lymphoma B cells (NHL-B), common B cell neoplasm that have been increasing in recent years. Although much of TRAF-6 functions have focused primarily as an adaptor molecule in signaling pathways in the cytoplasm, the role of TRAF-6 in other cellular compartments has not been investigated. Here, we demonstrate, by confocal microscopy as well as cellular fractionation studies that TRAF-6 resides not only in the cytoplasm but also in the nucleus of lymphoma B cells. Immunoprecipitation studies show that TRAF6 is auto-ubiquitinated in the cytoplasm but not in the nucleus, suggesting that nuclear TRAF6 functions differently than cytoplasmic TRAF6. Chromatin immunoprecipitation (ChiP) cloning assays using anti-TRAF6 polyclonal antibody reveal over 200 clones, one of which contains a 130 bp fragment belonging to the proximal 5′ end of the c-myb oncogene promoter. Further experiments demonstrate that nuclear TRAF6 co-localized with SUMO1 and c-myb, suggesting that TRAF-6 may enter the nucleus through SUMO1 interaction and serve as an E3 sumo ligase, in addition to its known adapter role in cytoplasmic signaling. Over-expression studies show that TRAF6 enhances c-myb sumoylation in lymphoma B cells, where this oncogene is over-expressed. C-myb correlates with TRAF6 protein and mRNA expressions in NHL-B cells, suggesting that TRAF6 may be involved in the modulation of c-myb expression through sumoylation, regulating key genes that are regulated by c-myb. Small interfering RNA (siRNA) targeting c-myb results in inhibition of lymphoma cell survival, suggesting that SUMO1/TRAF6/c-myb interactions are important in cell survival pathways in aggressive NHL-B. Such pathways could represent novel targets for the development of therapeutic agents for aggressive B cell lymphomas.
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Speiser, Daniel E., Soo Young Lee, Brian Wong, Joseph Arron, Angela Santana, Young-Yun Kong, Pamela S. Ohashi, and Yongwon Choi. "A Regulatory Role for TRAF1 in Antigen-induced Apoptosis of T Cells." Journal of Experimental Medicine 185, no. 10 (May 19, 1997): 1777–83. http://dx.doi.org/10.1084/jem.185.10.1777.
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Tumor necrosis factor receptor (TNFR)–associated factor 2 (TRAF2) and TRAF1 were found as components of the TNFR2 signaling complex, which exerts multiple biological effects on cells such as cell proliferation, cytokine production, and cell death. In the TNFR2-mediated signaling pathways, TRAF2 works as a mediator for activation signals such as NF-κB, but the role of TRAF1 has not been previously determined. Here we show in transgenic mice that TRAF1 overexpression inhibits antigen-induced apoptosis of CD8+ T lymphocytes. Our results demonstrate a biological role for TRAF1 as a regulator of apoptotic signals and also support the hypothesis that the combination of TRAF proteins in a given cell type determines distinct biological effects triggered by members of the TNF receptor superfamily.
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Mainou, Bernardo A., David N. Everly, and Nancy Raab-Traub. "Unique Signaling Properties of CTAR1 in LMP1-Mediated Transformation." Journal of Virology 81, no. 18 (July 11, 2007): 9680–92. http://dx.doi.org/10.1128/jvi.01001-07.
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ABSTRACT The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) gene is considered the EBV oncogene as it is necessary for EBV-mediated transformation of B lymphocytes and itself transforms rodent fibroblasts. LMP1 activates the NF-κB, phosphatidylinositol 3-kinase (PI3K)-Akt, mitogen-activated protein kinase, and Jun N-terminal protein kinase signaling pathways through its two signaling domains, carboxyl-terminal activating regions 1 and 2 (CTAR1 and CTAR2). CTAR1 and CTAR2 induce signal transduction pathways through their direct (CTAR1) or indirect (CTAR2) recruitment of tumor necrosis factor receptor-associated factors (TRAFs). CTAR1 is necessary for LMP1-mediated transformation as well as activation of PI3K signaling and induction of cell cycle markers associated with G1/S transition. In this study, activation of PI3K-Akt signaling and deregulation of cell cycle markers were mapped to the TRAF-binding domain within CTAR1 and to the residues between CTAR1 and CTAR2. LMP1 CTAR1 also activated the MEK1/2-extracellular signal-regulated kinase 1/2 signaling pathway, and this activation was necessary for LMP1-induced transformation of Rat-1 fibroblasts. Dominant-negative forms of TRAF2 and TRAF3 inhibited but did not fully block LMP1-mediated transformation. These findings identify a new signaling pathway that is uniquely activated by the TRAF-binding domain of LMP1 and is required for transformation.
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Hildebrand, Joanne, and Gail Bishop. "TRAF6, a new member of the proximal signaling complex recruited by BAFFR and TACI in B lymphocytes (34.1)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 34.1. http://dx.doi.org/10.4049/jimmunol.184.supp.34.1.
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Abstract The cytokines BAFF (B-cell activating factor of the TNF family, BLyS) and APRIL (a proliferation-inducing ligand) activate several major signaling cascades responsible for B-cell survival and homeostasis. Made primarily by myeloid cells, BAFF binds and activates three cell membrane receptors; BCMA (B-cell maturation antigen), TACI (transmembrane activator and CAML interactor), and BAFF-R (BAFF Receptor, BR3), while APRIL binds TACI and BCMA. Studies of genetically altered mice demonstrate that TACI and BCMA perform niche roles in B-cell Ig isotype switching and plasma cell maintenance. In contrast, BAFF-R deletion in mice results in greater than 90% loss of mature B-cells, revealing it as an essential mediator of B-cell maturation and survival beyond the immature transitional (T1) stage. TNF receptor family proteins utilize characteristic combinations of TNF receptor associated factors (TRAFs) to bridge receptor activation with a multitude of downstream signaling pathways. To date, studies of TRAF recruitment by TACI and BAFFR and their roles in signaling have been limited, and TRAF3 was the only TRAF thought to associate with these receptors. Here we present the novel finding that TRAF6 is directly recruited by TACI and BAFFR in B-cells, and that it forms an essential link to the initiation of the canonical NF-kB pathway and other pro survival signals.
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Leleu, Xavier, Lian Xu, Zachary R. Hunter, Anne-Sophie Moreau, Xiaoying Jia, Garrett O’Sullivan, Vinod Bakthavachalam, et al. "Abnormal Expression of TRAF Adapter Proteins in Waldenstrom’s Macroglobulinemia." Blood 108, no. 11 (November 16, 2006): 4640. http://dx.doi.org/10.1182/blood.v108.11.4640.4640.
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Abstract Background: Waldenström’s Macroglobulinemia (WM) is an incurable low-grade lymphoplasmacytic lymphoma with as yet unknown genetic basis for its pathogenesis. Several TNF family members (CD40L, APRIL and BAFF/BLYS) are known to regulate WM growth and survival. TRAFs are a novel family of adapter proteins that facilitate pro-apoptotic (TACI) or pro-survival/differentiation (CD40, BAFFR, BCMA) receptor signaling mediated by TNF family ligands. Therefore, understanding the TRAF system in WM may yield important clues about WM growth and survival. Methods: WM cell lines (BCWM.1 and WSU-WM), IgM secreting low-grade lymphoma cell lines (MEK1, RL, Namalwa), and primary bone marrow CD19+ selected lymphoplasmacytic cells (LPC) from 20 WM patients and 6 healthy donors were evaluated for TRAF (TRAF 2, 3, 5, 6) expression using semi quantitative RT-PCR and/or western blot analysis. Results: The TNF familiy receptors CD40, BAFFR, BCMA, and TACI were expressed in all cell lines tested as well as in CD19+ selected LPC from WM patients and healthy donors. Moreover, TRAF 2, 3, 5, 6 were expressed in all cell lines by both RT-PCR and western blot analysis. In contrast, we observed loss or abnormally low expression of both TRAF 2 and 5 in 6/20 (30%) patients, whilst TRAF 3 was absent or abnormally low in 3/30 (15%) patients. TRAF 6 was expressed in all patients. Among healthy donors, we observed expression of all TRAF adapter proteins. Conclusion: Up to one third of WM patients demonstrate loss of TRAF 2 and 5 adapter proteins which facilitate signaling through the pro-apoptotic receptor TACI. Ongoing studies including gene sequencing and siRNA knockdown models are delineating a role for TRAF loss in the pathogenesis of WM.
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Lee, Soo Young, Sang Yull Lee, and Yongwon Choi. "TRAF-interacting Protein (TRIP): A Novel Component of the Tumor Necrosis Factor Receptor (TNFR)- and CD30-TRAF Signaling Complexes That Inhibits TRAF2-mediated NF-κB Activation." Journal of Experimental Medicine 185, no. 7 (April 7, 1997): 1275–86. http://dx.doi.org/10.1084/jem.185.7.1275.
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Through their interaction with the TNF receptor–associated factor (TRAF) family, members of the tumor necrosis factor receptor (TNFR) superfamily elicit a wide range of biological effects including differentiation, proliferation, activation, or cell death. We have identified and characterized a novel component of the receptor–TRAF signaling complex, designated TRIP (TRAF-interacting protein), which contains a RING finger motif and an extended coiled-coil domain. TRIP associates with the TNFR2 or CD30 signaling complex through its interaction with TRAF proteins. When associated, TRIP inhibits the TRAF2-mediated NF-κB activation that is required for cell activation and also for protection against apoptosis. Thus, TRIP acts as a receptor–proximal regulator that may influence signals responsible for cell activation/proliferation and cell death induced by members of the TNFR superfamily.
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Wu, Siting, Mengshi Sun, Xin Zhang, Jiaming Liao, Mengke Liu, Qiwei Qin, and Jingguang Wei. "Grouper TRAF4, a Novel, CP-Interacting Protein That Promotes Red-Spotted Grouper Nervous Necrosis Virus Replication." International Journal of Molecular Sciences 22, no. 11 (June 7, 2021): 6136. http://dx.doi.org/10.3390/ijms22116136.
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Tumor necrosis factor receptor-associated factors (TRAFs) play important roles in the biological processes of immune regulation, the inflammatory response, and apoptosis. TRAF4 belongs to the TRAF family and plays a major role in many biological processes. Compared with other TRAF proteins, the functions of TRAF4 in teleosts have been largely unknown. In the present study, the TRAF4 homologue (EcTRAF4) of the orange-spotted grouper was characterized. EcTRAF4 consisted of 1413 bp encoding a 471-amino-acid protein, and the predicted molecular mass was 54.27 kDa. EcTRAF4 shares 99.79% of its identity with TRAF4 of the giant grouper (E. lanceolatus). EcTRAF4 transcripts were ubiquitously and differentially expressed in all the examined tissues. EcTRAF4 expression in GS cells was significantly upregulated after stimulation with red-spotted grouper nervous necrosis virus (RGNNV). EcTRAF4 protein was distributed in the cytoplasm of GS cells. Overexpressed EcTRAF4 promoted RGNNV replication during viral infection in vitro. Yeast two-hybrid and coimmunoprecipitation assays showed that EcTRAF4 interacted with the coat protein (CP) of RGNNV. EcTRAF4 inhibited the activation of IFN3, IFN-stimulated response element (ISRE), and nuclear factor-κB (NF-κB). Overexpressed EcTRAF4 also reduced the expression of interferon (IFN)-related molecules and pro-inflammatory factors. Together, these results demonstrate that EcTRAF4 plays crucial roles in RGNNV infection.
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Zhao, Bao-Sheng, Hai-Ru Huo, Yue-Ying Ma, Hong-Bin Liu, Lan-Fang Li, Feng Sui, Cang-Hai Li, Shu-Ying Guo, and Ting-Liang Jiang. "Effects of 3-Phenyl-Propenal on the Expression of Toll-Like Receptors and Downstream Signaling Components on Raw264.7 Murine Macrophages." American Journal of Chinese Medicine 36, no. 01 (January 2008): 159–69. http://dx.doi.org/10.1142/s0192415x08005679.
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3-phenyl-propenal is one of the principle compounds isolated from Guizhi (Ramulus Cinnamomi), the principal drug in Guizhi-Tang (GZT), a famous traditional Chinese medical formula. The aim of the present study was to investigate the effects of 3-phenyl-propenal on the expression of toll-like receptor 3 (TLR3), TLR4 and the downstream signaling components on Raw264.7 murine microphages. Raw264.7 cells were cultured in RPMI-1640 medium containing LPS (lipopolysaccharide) or poly (I:C) in the presence or absence of 3-phenyl-propenal. After 24-hour incubation, the medium was collected and the amount of TNF-α and IFN-β was measured by ELISA. mRNA expression of TLR3, TLR4, myeloid differentiation factor (MyD88), TRAF-6 (tumor necrosis factor receptor-associated), TRAM (toll-like receptor-associated molecule) and TRIF (TIR domain-containing adaptor inducing IFN-β) were analyzed by real-time PCR with SYBR green dye. Protein expression of TLR3 and TLR4 was analyzed by Western blotting and that of MyD88 and TRAF-6 was analyzed by immunofluorescence assay. The results indicate that LPS increased the expression of TLR4, MyD88, TRAF-6, TRAM and TRIF, but had no influence on TLR3, while poly (I:C) up-regulated the expression of TLR3, MyD88, TRAM and TRIF. 3-phenyl-propenal significantly decreased the expression of LPS-induced TLR4, MyD88, TRAF-6, while possessing no effect on LPS-induced TRAM and TRIF expression in Raw264.7 cells. When cells were stimulated by poly (I:C), 3-phenyl-propenal significantly decreased TLR3 and MyD88 expression. In conclusion, 3-phenyl-propenal blocked the over-expression of TLR3, TLR4, their downstream signaling components MyD88 and TRAF-6, which indicate that it had an antagonistic effect on TLR3 and TLR4.
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McGowan, Jenna, Cara Peter, Joshua Kim, Sonam Popli, Brent Veerman, Jessica Saul-McBeth, Heather Conti, Shondra M. Pruett-Miller, Saurabh Chattopadhyay, and Ritu Chakravarti. "14-3-3ζ–TRAF5 axis governs interleukin-17A signaling." Proceedings of the National Academy of Sciences 117, no. 40 (September 23, 2020): 25008–17. http://dx.doi.org/10.1073/pnas.2008214117.
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IL-17A is a therapeutic target in many autoimmune diseases. Most nonhematopoietic cells express IL-17A receptors and respond to extracellular IL-17A by inducing proinflammatory cytokines. The IL-17A signal transduction triggers two broad, TRAF6- and TRAF5-dependent, intracellular signaling pathways to produce representative cytokines (IL-6) and chemokines (CXCL-1), respectively. Our limited understanding of the cross-talk between these two branches has generated a crucial gap of knowledge, leading to therapeutics indiscriminately blocking IL-17A and global inhibition of its target genes. In previous work, we discovered an elevated expression of 14-3-3 proteins in inflammatory aortic disease, a rare human autoimmune disorder with increased levels of IL-17A. Here we report that 14-3-3ζ is essential for IL-17 signaling by differentially regulating the signal-induced IL-6 and CXCL-1. Using genetically manipulated human and mouse cells, and ex vivo and in vivo rat models, we uncovered a function of 14-3-3ζ. As a part of the molecular mechanism, we show that 14-3-3ζ interacts with several TRAF proteins; in particular, its interaction with TRAF5 and TRAF6 is increased in the presence of IL-17A. In contrast to TRAF6, we found TRAF5 to be an endogenous suppressor of IL-17A–induced IL-6 production, an effect countered by 14-3-3ζ. Furthermore, we observed that 14-3-3ζ interaction with TRAF proteins is required for the IL-17A–induced IL-6 levels. Together, our results show that 14-3-3ζ is an essential component of IL-17A signaling and IL-6 production, an effect that is suppressed by TRAF5. To the best of our knowledge, this report of the 14-3-3ζ-TRAF5 axis, which differentially regulates IL-17A–induced IL-6 and CXCL-1 production, is unique.
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Arron, Joseph R., Yael Pewzner-Jung, Matthew C. Walsh, Takashi Kobayashi, and Yongwon Choi. "Regulation of the Subcellular Localization of Tumor Necrosis Factor Receptor–associated Factor (TRAF)2 by TRAF1 Reveals Mechanisms of TRAF2 Signaling." Journal of Experimental Medicine 196, no. 7 (September 30, 2002): 923–34. http://dx.doi.org/10.1084/jem.20020774.
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Tumor necrosis factor receptor–associated factor (TRAF)2 is a critical adaptor molecule for tumor necrosis factor (TNF) receptors in inflammatory and immune signaling. Upon receptor engagement, TRAF2 is recruited to CD40 and translocates to lipid rafts in a RING finger-dependent process, which enables the activation of downstream signaling cascades including c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-κB. Although TRAF1 can displace TRAF2 and CD40 from raft fractions, it promotes the ability of TRAF2 activate signaling over a sustained period of time. Removal of the RING finger of TRAF2 prevents its translocation into detergent-insoluble complexes and renders it dominant negative for signaling. TRAF1−/− dendritic cells show attenuated responses to secondary stimulation by TRAF2-dependent factors and increased stimulus-dependent TRAF2 degradation. Replacement of the RING finger of TRAF2 with a raft-targeting signal restores JNK activation and association with the cyto-skeletal protein Filamin, but not NF-κB activation. These findings offer insights into the mechanism of TRAF2 signaling and identify a physiological role for TRAF1 as a regulator of the subcellular localization of TRAF2.
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Donners, Marjo M. P. C., Linda Beckers, Dirk Lievens, Imke Munnix, Johan Heemskerk, Ben J. Janssen, Erwin Wijnands, et al. "The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling." Blood 111, no. 9 (May 1, 2008): 4596–604. http://dx.doi.org/10.1182/blood-2007-05-088906.
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Abstract We investigated the role of CD40 and CD40L in neointima formation and identified the downstream CD40-signaling intermediates (tumor necrosis factor [TNF]–receptor associated factors [TRAF]) involved. Neointima formation was induced in wild-type, CD40−/−, CD40L−/−, and in CD40−/− mice that contained a CD40 transgene with or without mutations at the CD40-TRAF2,3&5, TRAF6, or TRAF2,3,5&6 binding sites. Compared with wild-type mice, CD40−/− mice showed a significant decrease in neointima formation with increased collagen deposition and decreased inflammatory cell infiltration. Neointima formation was also impaired in wild-type mice reconstituted with CD40−/− bone marrow. In vitro, the capacity of CD40−/− leukocytes to adhere to the endothelium was reduced. Ligated carotid arteries of CD40−/− mice showed a smaller total vessel volume and an impaired remodeling capacity, reflected by decreased gelatinolytic/collagenolytic activity. Comparable results were found in mice with defects in CD40-TRAF6 and CD40-TRAF 2/3/5&6 binding, but not in mice with defects in CD40-TRAF2/3&5 binding. Neointima formation and vascular remodeling in CD40-receptor–deficient mice is impaired, due to a decreased inflammatory cell infiltration and matrix-degrading protease activity, with CD40-TRAF6 signaling as the key regulator. This identifies the CD40-TRAF6 axis as a potential therapeutic target in vascular disease.
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Abell, Amy N., and Gary L. Johnson. "MEKK4 Is an Effector of the Embryonic TRAF4 for JNK Activation." Journal of Biological Chemistry 280, no. 43 (September 12, 2005): 35793–96. http://dx.doi.org/10.1074/jbc.c500260200.
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TRAF4 has previously been shown to activate JNK through an unknown mechanism. Here, we show that endogenous TRAF4 and MEKK4 associate in both human K562 cells and mouse E10.5 embryos. TRAF4 interacts with the kinase domain of MEKK4. However, this association does not require MEKK4 kinase activity. The interaction of MEKK4 and TRAF4 are further demonstrated by the colocalization of TRAF4 and MEKK4 in cells. Importantly, although TRAF4 has little or no ability to activate JNK independently, coexpression of TRAF4 and MEKK4 results in synergistic activation of JNK that is inhibited by a kinase-inactive mutant of MEKK4, MEKK4K1361R. MEKK4 binds the TRAF domain of TRAF4 and MEKK4/TRAF4 activation of JNK is inhibited by expression of the TRAF domain. Furthermore, TRAF4 stimulates MEKK4 kinase activity by promoting MEKK4 oligomerization and JNK activation can be stimulated by chemical induction of MEKK4 dimerization. The findings identify MEKK4 as the MAPK kinase kinase for TRAF4 regulation of the JNK pathway.
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Schwandner, Ralf, Kyoko Yamaguchi, and Zhaodan Cao. "Requirement of Tumor Necrosis Factor Receptor–Associated Factor (Traf)6 in Interleukin 17 Signal Transduction." Journal of Experimental Medicine 191, no. 7 (April 3, 2000): 1233–40. http://dx.doi.org/10.1084/jem.191.7.1233.
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Signaling through its widely distributed cell surface receptor, interleukin (IL)-17 enhances the transcription of genes encoding proinflammatory molecules. Although it has been well documented that IL-17 activates the transcription factor nuclear factor (NF)-κB and c-Jun NH2-terminal kinase (JNK), the upstream signaling events are largely unknown. Here we report the requirement of tumor necrosis factor receptor–associated factor (TRAF)6 in IL-17–induced NF-κB and JNK activation. In embryonic fibroblasts (EFs) derived from TRAF6 knockout mice, IL-17 failed to activate the IκB kinases (IKKs) and JNK. Consequently, IL-17–induced IL-6 and intercellular adhesion molecule 1 expression in the TRAF6-deficient cells was abolished. Lack of TRAF6 appeared to be the sole defect responsible for the observed failure to respond to IL-17, because transient transfection of TRAF6 expression plasmid into the TRAF6-deficient cells restored IL-17–induced NF-κB activation in a luciferase reporter assay. Furthermore, the levels of IL-17 receptor (IL-17R) on the TRAF6-deficient EFs were comparable to those on the wild-type control cells. Defect in IL-17 response was not observed in TRAF2-deficient EFs. Moreover, when TRAF6 and IL-17R were coexpressed in 293 cells, TRAF6 coimmunoprecipitated with IL-17R. Together, these results indicate that TRAF6, but not TRAF2, is a crucial component in the IL-17 signaling pathway leading to proinflammatory responses.
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Qu, Xinyan, Robert D. Stout, and Jill Suttles. "Modification of DC function via blockade of CD40:TRAF interactions (91.13)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 91.13. http://dx.doi.org/10.4049/jimmunol.182.supp.91.13.
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Abstract Ligation of CD40 on dendritic cells (DC) results in rapid protein kinase and transcription factor activation leading to enhanced expression of genes encoding a variety of cytokines and costimulatory molecules. CD40 does not contain cytoplasmic sequences with catalytic activity and transmits signals relying on the use of TNFR-associated factors (TRAFs), a family of adapter proteins that are involved in signaling by the TNF receptor family and the toll/interleukin-1 receptor (TIR) family members. Cell-permeable TRAF6 and TRAF2/3/5 blocking peptides (TRAFBPs) corresponding to the TRAF6 or TRAF2/3/5 binding region of CD40 were employed to better define the roles of TRAF2 and TRAF6 in CD40 signaling in DC. Both TRAF6BP and TRAF2BP inhibited CD40-stimulated DC production of TNF and IL-6, but did not impact CCL2 and CXCL8 production. ERK1/2 phosphorylation was inhibited by both TRAF6BP and TRAF2BPs, whereas JNK, p65 and AKT phosphorylation were abrogated by TRAF6, but not by TRAF2BP. Both TRAF6BP and TRAF2BP have no effect on p38 MAP kinase activation. During antigen presentation to T cells, pre-incubation of DC with TRAF6BP and TRAF2BP effectively inhibited Th1 and Th17 differentiation, but did not impact activation of IL-10-producing T cells. Thus, targeting TRAF:CD40 interactions in DC may provide a means to selectively modulate DC function.