tnf receptor associated factor 3


Summary: A signal transducing tumor necrosis factor receptor associated factor that is involved in regulation of NF-KAPPA B signaling and activation of MITOGEN-ACTIVATED PROTEIN KINASES.

Top Publications

  1. Hacker H, Redecke V, Blagoev B, Kratchmarova I, Hsu L, Wang G, et al. Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature. 2006;439:204-7 pubmed
  2. Ni C, Oganesyan G, Welsh K, Zhu X, Reed J, Satterthwait A, et al. Key molecular contacts promote recognition of the BAFF receptor by TNF receptor-associated factor 3: implications for intracellular signaling regulation. J Immunol. 2004;173:7394-400 pubmed
    ..The structure of the complex provides a molecular explanation for binding affinities and selective protein interactions in TNFR-TRAF interactions. ..
  3. Saha S, Pietras E, He J, Kang J, Liu S, Oganesyan G, et al. Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif. EMBO J. 2006;25:3257-63 pubmed
    ..Thus, our findings suggest that the direct and specific interaction between the TRAF domain of TRAF3 and the TIM of Cardif is required for optimal Cardif-mediated antiviral responses. ..
  4. Dadgostar H, Cheng G. Membrane localization of TRAF 3 enables JNK activation. J Biol Chem. 2000;275:2539-44 pubmed
  5. Ni C, Welsh K, Leo E, Chiou C, Wu H, Reed J, et al. Molecular basis for CD40 signaling mediated by TRAF3. Proc Natl Acad Sci U S A. 2000;97:10395-9 pubmed
    ..TRAF2 suggests that CD40 may assume different conformations when bound to different TRAF family members. This molecular adaptation may influence binding affinity and specific cellular triggers. ..
  6. Vallabhapurapu S, Matsuzawa A, Zhang W, Tseng P, Keats J, Wang H, et al. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nat Immunol. 2008;9:1364-70 pubmed publisher
    ..Constitutive activation of this pathway causes perinatal lethality and lymphoid defects. ..
  7. Kayagaki N, Phung Q, Chan S, Chaudhari R, Quan C, O Rourke K, et al. DUBA: a deubiquitinase that regulates type I interferon production. Science. 2007;318:1628-32 pubmed
    ..A discrete ubiquitin interaction motif within DUBA was required for efficient deubiquitination of TRAF3 and optimal suppression of IFN-I. Our data identify DUBA as a negative regulator of innate immune responses. ..
  8. Mukundan L, Bishop G, Head K, Zhang L, Wahl L, Suttles J. TNF receptor-associated factor 6 is an essential mediator of CD40-activated proinflammatory pathways in monocytes and macrophages. J Immunol. 2005;174:1081-90 pubmed
    ..These data demonstrate that TRAF6 acts as a critical adapter of both the Src/ERK1/2 and IKK/NF-kappaB proinflammatory signaling pathways in monocytes and macrophages. ..
  9. Keats J, Fonseca R, Chesi M, Schop R, Baker A, Chng W, et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell. 2007;12:131-44 pubmed
    ..These results highlight the critical importance of the NF-kappaB pathway in the pathogenesis of multiple myeloma. ..

More Information


  1. Hostager B, Catlett I, Bishop G. Recruitment of CD40 and tumor necrosis factor receptor-associated factors 2 and 3 to membrane microdomains during CD40 signaling. J Biol Chem. 2000;275:15392-8 pubmed
  2. Hauer J, PĆ¼schner S, Ramakrishnan P, Simon U, Bongers M, Federle C, et al. TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappaB pathway by TRAF-binding TNFRs. Proc Natl Acad Sci U S A. 2005;102:2874-9 pubmed
  3. Oganesyan G, Saha S, Guo B, He J, Shahangian A, Zarnegar B, et al. Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature. 2006;439:208-11 pubmed
    ..Our data demonstrate that TRAF3 is a major regulator of type I IFN production and the innate antiviral response. ..
  4. He J, Saha S, Kang J, Zarnegar B, Cheng G. Specificity of TRAF3 in its negative regulation of the noncanonical NF-kappa B pathway. J Biol Chem. 2007;282:3688-94 pubmed
    ..Our studies suggest that both the RING finger domain activity and the specific binding of the TRAF domain to NIK are two critical components of TRAF3 suppression of NIK protein levels and the processing of p100 to p52. ..
  5. Annunziata C, Davis R, Demchenko Y, Bellamy W, Gabrea A, Zhan F, et al. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell. 2007;12:115-30 pubmed
    ..These data demonstrate that addiction to the NF-kappaB pathway is frequent in myeloma and suggest that IKKbeta inhibitors hold promise for the treatment of this disease. ..
  6. VanArsdale T, VanArsdale S, Force W, Walter B, Mosialos G, Kieff E, et al. Lymphotoxin-beta receptor signaling complex: role of tumor necrosis factor receptor-associated factor 3 recruitment in cell death and activation of nuclear factor kappaB. Proc Natl Acad Sci U S A. 1997;94:2460-5 pubmed
    ..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. ..
  7. Li C, Ni C, Havert M, Cabezas E, He J, Kaiser D, et al. Downstream regulator TANK binds to the CD40 recognition site on TRAF3. Structure. 2002;10:403-11 pubmed
    ..Binding affinity, measured by isothermal titration calorimetry and competition assays, demonstrated that TANK competes with CD40 for the TRAF binding site. ..
  8. Xu L, Shu H. TNFR-associated factor-3 is associated with BAFF-R and negatively regulates BAFF-R-mediated NF-kappa B activation and IL-10 production. J Immunol. 2002;169:6883-9 pubmed
    ..Moreover, overexpression of TRAF3 inhibits BAFF-R-mediated NF-kappaB activation and IL-10 production. Taken together, our findings suggest that TRAF3 is a negative regulator of BAFF-R-mediated NF-kappaB activation and IL-10 production. ..
  9. He L, Grammer A, Wu X, Lipsky P. TRAF3 forms heterotrimers with TRAF2 and modulates its ability to mediate NF-{kappa}B activation. J Biol Chem. 2004;279:55855-65 pubmed
    ..Together, these results reveal a novel association between TRAF2 and TRAF3 that is mediated by unique portions of each protein and that specifically regulates activation of NF-kappaB, but not AP-1. ..
  10. Hu H, O Rourke K, Boguski M, Dixit V. A novel RING finger protein interacts with the cytoplasmic domain of CD40. J Biol Chem. 1994;269:30069-72 pubmed
    ..This is the first identification of a molecule that interacts with CD40 and whose sequence suggests a potential role in signaling. ..
  11. Busch L, Bishop G. Multiple carboxyl-terminal regions of the EBV oncoprotein, latent membrane protein 1, cooperatively regulate signaling to B lymphocytes via TNF receptor-associated factor (TRAF)-dependent and TRAF-independent mechanisms. J Immunol. 2001;167:5805-13 pubmed
    ..Furthermore, we find that the function of CTAR1, but not CTAR2, correlates with TRAF binding and present evidence that as yet unidentified cytoplasmic proteins may associate with LMP1 to mediate some of its signaling activities. ..
  12. He J, Zarnegar B, Oganesyan G, Saha S, Yamazaki S, Doyle S, et al. Rescue of TRAF3-null mice by p100 NF-kappa B deficiency. J Exp Med. 2006;203:2413-8 pubmed
  13. Bishop G, Xie P. Multiple roles of TRAF3 signaling in lymphocyte function. Immunol Res. 2007;39:22-32 pubmed
    ..TRAF3 is also important for signaling via innate immune receptors, as well as an oncogenic mimic of a normal receptor that is implicated in promoting both malignancies and autoimmunity. ..
  14. Wu S, Xie P, Welsh K, Li C, Ni C, Zhu X, et al. LMP1 protein from the Epstein-Barr virus is a structural CD40 decoy in B lymphocytes for binding to TRAF3. J Biol Chem. 2005;280:33620-6 pubmed
  15. Michallet M, Meylan E, Ermolaeva M, Vazquez J, Rebsamen M, Curran J, et al. TRADD protein is an essential component of the RIG-like helicase antiviral pathway. Immunity. 2008;28:651-61 pubmed publisher
    ..Thus, TRADD is not only an essential component of proinflammatory TNFRI signaling, but is also required for RLH-Cardif-dependent antiviral immune responses. ..
  16. Cheng G, Cleary A, Ye Z, Hong D, Lederman S, Baltimore D. Involvement of CRAF1, a relative of TRAF, in CD40 signaling. Science. 1995;267:1494-8 pubmed
    ..It is likely that other members of the TNF receptor superfamily use CRAF-related proteins in their signal transduction processes. ..
  17. Hostager B, Haxhinasto S, Rowland S, Bishop G. Tumor necrosis factor receptor-associated factor 2 (TRAF2)-deficient B lymphocytes reveal novel roles for TRAF2 in CD40 signaling. J Biol Chem. 2003;278:45382-90 pubmed
    ..These findings demonstrate previously unappreciated roles for TRAF2 in signaling by TNF receptor family members, using an approach that facilitates the analysis of genes critical to the viability of whole organisms. ..
  18. Tsukamoto N, Kobayashi N, Azuma S, Yamamoto T, Inoue J. Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40. Proc Natl Acad Sci U S A. 1999;96:1234-9 pubmed
    ..These results indicate that NFkappaB activating signals emanating from cyt-N and cyt-C are mediated by the different members of the TRAF family and could be regulated in a distinct manner. ..
  19. Hostager B, Bishop G. Cutting edge: contrasting roles of TNF receptor-associated factor 2 (TRAF2) and TRAF3 in CD40-activated B lymphocyte differentiation. J Immunol. 1999;162:6307-11 pubmed
    ..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. ..
  20. Zarnegar B, Yamazaki S, He J, Cheng G. Control of canonical NF-kappaB activation through the NIK-IKK complex pathway. Proc Natl Acad Sci U S A. 2008;105:3503-8 pubmed publisher
    ..Thus, our data demonstrate that inhibition of TRAF3 results in coordinated activation of both NF-kappaB activation pathways. ..
  21. Liao G, Zhang M, Harhaj E, Sun S. Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J Biol Chem. 2004;279:26243-50 pubmed
    ..These results suggest that induction of noncanonical NF-kappaB signaling may involve the rescue of NIK from TRAF3-mediated negative regulation. ..
  22. Gardam S, Sierro F, Basten A, Mackay F, Brink R. TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor. Immunity. 2008;28:391-401 pubmed publisher
    ..This process was TRAF2 dependent, revealing dual roles for TRAF2 in regulating B cell homeostasis. ..
  23. Zirlik A, Bavendiek U, Libby P, MacFarlane L, Gerdes N, Jagielska J, et al. TRAF-1, -2, -3, -5, and -6 are induced in atherosclerotic plaques and differentially mediate proinflammatory functions of CD40L in endothelial cells. Arterioscler Thromb Vasc Biol. 2007;27:1101-7 pubmed
    ..These results implicate endothelial TRAF-1, -2, -3, -5, and -6 in CD40 signaling in atherogenesis, identifying these molecules as potential targets for selective therapeutic intervention. ..
  24. Brown K, Hostager B, Bishop G. Differential signaling and tumor necrosis factor receptor-associated factor (TRAF) degradation mediated by CD40 and the Epstein-Barr virus oncoprotein latent membrane protein 1 (LMP1). J Exp Med. 2001;193:943-54 pubmed
    ..This suggests that LMP1 utilizes a modified CD40 signaling pathway. Failure to regulate TRAFs may contribute to the enhanced capacity of LMP1 to activate B cells as well as promote B cell transformation. ..
  25. Urbich C, Mallat Z, Tedgui A, Clauss M, Zeiher A, Dimmeler S. Upregulation of TRAF-3 by shear stress blocks CD40-mediated endothelial activation. J Clin Invest. 2001;108:1451-8 pubmed
    ..Thus, upregulation of TRAF-3 represents a novel mechanism for preserving the functional integrity of the endothelial monolayer. ..
  26. Grech A, Amesbury M, Chan T, Gardam S, Basten A, Brink R. TRAF2 differentially regulates the canonical and noncanonical pathways of NF-kappaB activation in mature B cells. Immunity. 2004;21:629-42 pubmed
    ..This dual functionality explains the contrasting roles of TRAF2 in B cell maturation and activation. ..
  27. Guasparri I, Wu H, Cesarman E. The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling. EMBO Rep. 2006;7:114-9 pubmed publisher
    ..TRAF2, but not TRAF3, mediates the association of vFLIP with the IkappaB kinase complex. These data indicate that vFLIP uses TRAF2 and TRAF3 for signalling to NF-kappaB, which is crucial for KSHV-associated lymphomagenesis...
  28. Jang I, Lee Z, Kim Y, Kim S, Kwon B. Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B. Biochem Biophys Res Commun. 1998;242:613-20 pubmed
    ..4-1BB-mediated NF-kappa B activation was inhibited by a dominant negative-TRAF2 or -NF-kappa B-inducing kinase (NIK). These data suggest that 4-1BB functions may be mediated by NF-kappa B activation, which requires a TRAF2/NIK pathway. ..
  29. Wood E, Crosby R, Dickerson S, Frye S, Griffin R, Hunter R, et al. A prodrug approach to the design of cRaf1 kinase inhibitors with improved cellular activity. Anticancer Drug Des. 2001;16:1-6 pubmed
    ..Many phenol isosteres were synthesized and tested, but failed to provide adequate enzyme potency. A prodrug approach resulted in a 2- to 17-fold improvement over the parent compound in cell-based efficacy. ..
  30. Lutgens E, Lievens D, Beckers L, Wijnands E, Soehnlein O, Zernecke A, et al. Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile. J Exp Med. 2010;207:391-404 pubmed publisher
  31. Bradley J, Pober J. Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene. 2001;20:6482-91 pubmed
    ..TRAF proteins are expressed in normal and diseased tissue in a regulated fashion, suggesting that they play an important role in physiological and pathological processes. ..
  32. Ikeda O, Sekine Y, Yasui T, Oritani K, Sugiyma K, Muromoto R, et al. STAP-2 negatively regulates both canonical and noncanonical NF-kappaB activation induced by Epstein-Barr virus-derived latent membrane protein 1. Mol Cell Biol. 2008;28:5027-42 pubmed publisher
    ..Finally, STAP-2 knockout mouse embryonic fibroblasts showed enhanced LMP1-induced cell growth. These results suggest that STAP-2 acts as an endogenous negative regulator of EBV LMP1-mediated signaling through TRAF3 and TRADD...
  33. Sun S, Ley S. New insights into NF-kappaB regulation and function. Trends Immunol. 2008;29:469-78 pubmed publisher
    ..New research has also identified several novel regulatory proteins that control the transcriptional activity of nuclear NF-kappaB. ..
  34. Siemienski K, Peters N, Scheurich P, Wajant H. Organization of the human tumour necrosis factor receptor-associated factor 1 (TRAF1) gene and mapping to chromosome 9q33-34. Gene. 1997;195:35-9 pubmed
    ..The putative promotor region of the TRAFI gene was isolated by use of a PCR-based genomic walking approach. Fluorescence in situ hybridization was used to map this gene to chromosome 9q33-34. ..
  35. Johnsen I, Nguyen T, Bergstroem B, Fitzgerald K, Anthonsen M. The tyrosine kinase c-Src enhances RIG-I (retinoic acid-inducible gene I)-elicited antiviral signaling. J Biol Chem. 2009;284:19122-31 pubmed publisher
    ..The interaction between c-Src and TRAF3 was found to occur within the RING domain of TRAF3. Taken together, our results suggest that c-Src enhances RIG-I-mediated signaling, acting at the level of TRAF3. ..
  36. Mainou B, Everly D, Raab Traub N. Unique signaling properties of CTAR1 in LMP1-mediated transformation. J Virol. 2007;81:9680-92 pubmed
    ..These findings identify a new signaling pathway that is uniquely activated by the TRAF-binding domain of LMP1 and is required for transformation...
  37. He J, Oganesyan G, Saha S, Zarnegar B, Cheng G. TRAF3 and its biological function. Adv Exp Med Biol. 2007;597:48-59 pubmed
    ..Namely, TRAF3 functions as a negative regulator of the NF-kappaB pathway and separately, as a positive regulator of type I IFN production, placing itself as a critical regulator of both innate and adaptive immune responses. ..
  38. Lavorgna A, De Filippi R, Formisano S, Leonardi A. TNF receptor-associated factor 1 is a positive regulator of the NF-kappaB alternative pathway. Mol Immunol. 2009;46:3278-82 pubmed publisher
    ..Collectively these results support a role for TRAF1 as a positive regulator of the NF-kappaB alternative pathway. ..
  39. von Grotthuss M, Wyrwicz L, Rychlewski L. mRNA cap-1 methyltransferase in the SARS genome. Cell. 2003;113:701-2 pubmed
    ..Based on the conservation of a characteristic tetrad of residues, the mRNA cap-1 methyltransferase function has been assigned to this protein, which has potential implications for antiviral therapy. ..
  40. Morse M, Clay T, Colling K, Lyerly H. Preparation of peptide-loaded dendritic cells for cancer immunotherapy. Mol Biotechnol. 2003;25:95-9 pubmed
    ..We describe the scheme that we are currently using to generate peptide-loaded dendritic cells for our clinical trials of cancer immunotherapy. ..
  41. Elmetwali T, Young L, Palmer D. CD40 ligand-induced carcinoma cell death: a balance between activation of TNFR-associated factor (TRAF) 3-dependent death signals and suppression of TRAF6-dependent survival signals. J Immunol. 2010;184:1111-20 pubmed publisher
    ..These data provide mechanistic insights into the consequences of CD40 activation in carcinoma cells and how these might be exploited in the clinical development of CD40-targeted anticancer therapies. ..
  42. Yamamoto H, Kishimoto T, Minamoto S. NF-kappaB activation in CD27 signaling: involvement of TNF receptor-associated factors in its signaling and identification of functional region of CD27. J Immunol. 1998;161:4753-9 pubmed
  43. Kim H, Lee D, Shin J, Lee Y, Jeon Y, Chung C, et al. Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase. FEBS Lett. 1999;443:297-302 pubmed
    ..The domain responsible for JNK activation was localized to the same region where TRAF1, 2, 3, and 6 bound, which suggests that these TRAF molecules might mediate the RANK-induced JNK activation. ..
  44. Lee Z, Lee S, Kwack K, Yeo W, Lee T, Bae S, et al. Caspase-mediated cleavage of TRAF3 in FasL-stimulated Jurkat-T cells. J Leukoc Biol. 2001;69:490-6 pubmed
    ..These findings suggest that TRAF3 may be regulated by caspases during apoptosis of T cells. ..
  45. Benson R, Hostager B, Bishop G. Rapid CD40-mediated rescue from CD95-induced apoptosis requires TNFR-associated factor-6 and PI3K. Eur J Immunol. 2006;36:2535-43 pubmed
    ..In contrast, CD40 rescue was completely abrogated in TRAF6-deficient B cells, which showed reduced activation of Akt in response to CD40 engagement. These results reveal a new rapid mechanism to balance B cell activation and apoptosis. ..
  46. Tohgo A, Pierce K, Choy E, Lefkowitz R, Luttrell L. beta-Arrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK-mediated transcription following angiotensin AT1a receptor stimulation. J Biol Chem. 2002;277:9429-36 pubmed
    ..These data demonstrate that beta-arrestins facilitate GPCR-mediated ERK activation but inhibit ERK-dependent transcription by binding to phospho-ERK1/2, leading to its retention in the cytosol. ..
  47. Rothenberger S, Rousseaux M, Knecht H, Bender F, Legler D, Bron C. Association of the Epstein-Barr virus latent membrane protein 1 with lipid rafts is mediated through its N-terminal region. Cell Mol Life Sci. 2002;59:171-80 pubmed
    ..Moreover, Ndelta25 inhibited WT LMP1-mediated induction of the transcription factors NF-kappaB and AP-1. Morphological data indicate that Ndelta25 hampers WT LMP1 plasma membrane localization, thus blocking LMP1 function. ..
  48. Yasui T, Muraoka M, Takaoka Shichijo Y, Ishida I, Takegahara N, Uchida J, et al. Dissection of B cell differentiation during primary immune responses in mice with altered CD40 signals. Int Immunol. 2002;14:319-29 pubmed
    ..We conclude that combinations of these two signals determine which of the extrafollicular or the follicular (GC) differentiation pathway B cells enter. ..
  49. Brown S, Richards C, Hanscom H, Feng S, Winkles J. The Fn14 cytoplasmic tail binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-kappaB activation. Biochem J. 2003;371:395-403 pubmed
    ..These results indicate that Fn14 is a functional TWEAK receptor that can associate with four distinct TRAF family members and stimulate the NF-kappaB transcription factor signalling pathway. ..
  50. Haxhinasto S, Bishop G. A novel interaction between protein kinase D and TNF receptor-associated factor molecules regulates B cell receptor-CD40 synergy. J Immunol. 2003;171:4655-62 pubmed
    ..Interestingly, the role of PKD was dependent upon the association of CD40 with TRAF2, and was inhibited by the binding of TRAF3, revealing a novel functional link between these two classes of signaling molecules. ..
  51. Kuai J, Nickbarg E, Wooters J, Qiu Y, Wang J, Lin L. Endogenous association of TRAF2, TRAF3, cIAP1, and Smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis. J Biol Chem. 2003;278:14363-9 pubmed
    ..Their association with LT beta R was further confirmed by coimmunoprecipitation in U937 cells and HEK293 cells. The presence of cIAP1 and Smac in LIGHT.LT beta R complex revealed a novel mechanism of LIGHT.LT beta R-induced apoptosis. ..
  52. Chan T, Gardam S, Gatto D, Turner V, Silke J, Brink R. In vivo control of B-cell survival and antigen-specific B-cell responses. Immunol Rev. 2010;237:90-103 pubmed publisher