Disease relevance of TRAF3

• Latent infection membrane protein 1 (LMP1), the Epstein-Barr virus transforming protein, associates with tumor necrosis factor receptor (TNFR) associated factor 1 (TRAF1) and TRAF3 [1].
• Prevention of TRAF3 proteolysis may be an entry point for design of novel pharmaceuticals to treat Hodgkin disease and immune system disorders [2].
• Ligation of the lymphotoxin-beta receptor (LTbetaR) recruits tumor necrosis factor receptor-associated factor-3 (TRAF3) and initiates cell death in HT29 adenocarcinoma cells [3].
• 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 [4].
• However, when RAS is mutated in melanoma, the cells switch their signaling from BRAF to CRAF [5].

High impact information on TRAF3

• These TRAF proteins, with the exception of TRAF3, are required for NF kappa B activation [6].
• Upregulation of TRAF-3 by shear stress blocks CD40-mediated endothelial activation [7].
• Thus, upregulation of TRAF-3 represents a novel mechanism for preserving the functional integrity of the endothelial monolayer [7].
• Shear stress specifically upregulates TRAF-3 in cultured endothelial cells [7].
• When autologous Epstein-Barr virus (EBV)-transformed B cells were either incubated with CAP-1 peptide or transduced with the CEA gene using a retroviral vector, they were lysed by the V24T cell line, but allogeneic non-A2 EBV-transformed B cells were not [8].

Chemical compound and disease context of TRAF3

• In Melanoma, RAS Mutations Are Accompanied by Switching Signaling from BRAF to CRAF and Disrupted Cyclic AMP Signaling [5].
• Twenty-five patients with stage Ic-II ovarian cancer (8 stage Ic and 17 stage IIb-c) were treated with total removal followed by 6 cycles of chemotherapy consisting of cyclophosphamide, doxorubicin, and cisplatin intravenously on day 1, every 4 weeks (CAP-1) [9].
• Twenty-five patients with stage Ic-II ovarian cancer (8 stage Ic and 17 stage IIb-c) were treated with total tumor removal followed by six cycles of chemotherapy consisting of cyclophosphamide, doxorubicin, and cisplatin (CAP-1) i.v. on day 1, every 4 weeks [10].

Biological context of TRAF3

• This inhibitory effect of TRAF3 depends on the presence of an intact zinc finger domain [11].
• Our findings provide evidence that a MC159/TRAF2/TRAF3 complex regulates a new aspect of Fas signaling, and identify MC159 FLIP as a molecule that targets multiple features of Fas-induced cell death [12].
• The TRAF3-binding site of human molluscipox virus FLIP molecule MC159 is critical for its capacity to inhibit Fas-induced apoptosis [12].
• Localization of the major NF-kappaB-activating site and the sole TRAF3 binding site of LMP-1 defines two distinct signaling motifs [13].
• The TRAF3 molecule interacts with the cytoplasmic carboxyl terminus (COOH terminus) of the Epstein-Barr virus-encoded oncogene LMP-1 [13].

Anatomical context of TRAF3

• In contrast, TRAF3 was not expressed in the HD cell lines [14].
• Peripheral blood lymphocytes were mostly TRAF-3 immunonegative, while granulocytes were TRAF-3 immunopositive [15].
• Plasma cells, however, were strongly TRAF-3 positive [15].
• Monocytes were strongly immunostained for TRAF-3, but macrophages in nodes typically contained little or no TRAF-3 immunoreactivity [15].
• Lymphocytes in the bone marrow were also typically TRAF-3 immunonegative, whereas myeloid progenitor cells and megakaryocytes were often TRAF-3 positive [15].

Associations of TRAF3 with chemical compounds

• Alanine substitution and truncation mutants of the human CD40ct domain were generated, revealing residues critical for binding TRAF2, TRAF3, or both of these proteins [16].
• Full-length TRAF3 and TRAF5 formed hetero-oligomers, presumably through their predicted isoleucine zippers [17].
• Tumor necrosis factor receptor-associated factor (TRAF)-1, TRAF-2, and TRAF-3 interact in vivo with the CD30 cytoplasmic domain; TRAF-2 mediates CD30-induced nuclear factor kappa B activation [18].
• The cytokine profile of CAP1- and CAP1-6D-specific CTL is consistent with a Tc1-type CTL [19].
• Tat as well as soluble CD154 (sCD154) prevented vincristineinduced reduction of TRAF-3 in KS cells transfected with a vector for neomycin resistance (KS psv-neo), but not in KS sCD40 [20].

Physical interactions of TRAF3

• 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 [21].
• In this study, we report the crystal structure of a 24-residue fragment of the cytoplasmic portion of BAFF-R bound in complex with TRAF3 [22].

Regulatory relationships of TRAF3

• The stability of TRAF3 regulates CD40/NF-kappa B-mediated control of the immune response, which is central to the biologic activity of the Reed-Sternberg cell [2].
• Further, stable overexpression of a TRAF3 mutant that lacks the RING and zinc finger domains inhibits LTbeta R-mediated cell death [23].
• Moreover, overexpression of TRAF3 inhibits BAFF-R-mediated NF-kappaB activation and IL-10 production [24].
• LMP1 associated enhanced expression of membrane CD25 and soluble CD25 may have immunomodulatory functions and could be involved in biology of EBV-associated diseases [25].

Other interactions of TRAF3

• These results suggest that TRAF5 and TRAF3 could be involved in both common and distinct signaling pathways emanating from CD40 [26].
• In addition, the introduction of TRAF3 together with the dominant negative mutants of TRAF2 or TRAF5 further reduced NF-kappaB activation [27].
• Key molecular contacts promote recognition of the BAFF receptor by TNF receptor-associated factor 3: implications for intracellular signaling regulation [22].
• Using a Hodgkin cell line, this study demonstrates that CD40 activation of NF-kappa B is mediated by proteolysis of TRAF3 [2].
• The full-length human CD40ct, the first 35 amino acids of the CD40ct encompassing the TRAF6 binding site (1-35), and amino acids 35-53 containing the TRAF2/TRAF3 binding domain were expressed in human lung fibroblasts as fusion proteins with the extracellular domain of human CD8alpha by retroviral transduction [28].

Analytical, diagnostic and therapeutic context of TRAF3

• Stimulation of PBLs with anti-CD3 Ab induced marked increases in the steady state levels of TRAF-3 protein in vitro as determined by immunoblotting, while levels of TRAF-2 were unchanged, implying a dynamic regulation of TRAF-3 expression [15].
• These results implicate TRAF3 as a critical component of the LTbeta R death signaling complex and indicate that at least two independent signaling pathways are initiated by LTbeta R ligation [23].
• Coimmunoprecipitation and confocal microscopy mapped the TRAF3 binding site to amino acids PEEGDPG at position 389 [29].
• Moreover parallel changes in subcellular distribution of TRAF2 and TRAF3 were recorded by electron microscopy [30].
• Crystallization and preliminary X-ray analysis of the TRAF domain of TRAF3 [31].

References