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Gene Review

TRAF1  -  TNF receptor-associated factor 1

Homo sapiens

Synonyms: EBI6, Epstein-Barr virus-induced protein 6, MGC:10353
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Disease relevance of TRAF1


High impact information on TRAF1

  • However, the molecules that initiate these signaling events, including the death domain- and TNF receptor associated factor (TRAF) domain-containing adapter proteins and the signaling enzymes associated with them, are largely unique to the TNF/nerve growth factor receptor family [5].
  • The stronger affinity and unique specificity of the TRADD-TRAF2 interaction are crucial for the suppression of apoptosis and provide a mechanistic basis for the perturbation of TRAF recruitment in sensitizing cell death induction [6].
  • The c-IAPs do not directly contact TNFR2, but rather associate with TRAF1 and TRAF2 through their N-terminal BIR motif-comprising domain [7].
  • These findings indicate that TRAF proteins may function as signal transducers for distinct receptor families and that TRAF6 participates in IL-1 signalling [8].
  • CD40-mediated regulation of immune responses by TRAF-dependent and TRAF-independent signaling mechanisms [9].

Biological context of TRAF1

  • The amino terminus has a RING finger domain, a cluster of zinc fingers and a coiled-coil domain, which are also present in other members of the TRAF family protein except for TRAF1 [10].
  • Thus, although our study revealed a common expression pattern of NF-kappaB/Rel-regulated inhibitors of apoptosis, our findings indicate an IKK-independent regulation of TRAF1 in B-CLL [3].
  • Association of c-IAP1 with the CD40 cytoplasmic domain complex was indirect and dependent on the presence of an intact TRAF1/2/3 binding site [11].
  • Cell death induced by other death receptor-independent stimuli such as cisplatin, staurosporine, and UV irradiation did not result in cleavage of TRAF1, and overexpression of the C-terminal TRAF1 fragment did not enhance cell death in these cases [12].
  • Organization of the human tumour necrosis factor receptor-associated factor 1 (TRAF1) gene and mapping to chromosome 9q33-34 [13].

Anatomical context of TRAF1


Associations of TRAF1 with chemical compounds

  • The known IKK inhibitor sulfasalazine did not compromise TRAF1 expression [3].
  • Here we show that TRAF1 is cleaved by caspase-8 into two fragments during apoptosis induced by TNF [18].
  • Here, we found that the PKC activators, phorbol 12-myristate 13-acetate (PMA) and bryostatin I, induced TRAF1 mRNA expression; pretreatment with actinomycin D blocked PMA-mediated TRAF1 expression suggesting induction at the transcriptional level [19].
  • Various PKC isoform-selective inhibitors blocked PMA-mediated TRAF1 mRNA and promoter stimulation; rottlerin, a selective PKCdelta inhibitor, had no effect suggesting that Ca(2+)-dependent PKC isoforms (e.g., PKCalpha and betaI) play a role in TRAF1 regulation [19].
  • In vitro, TRAF1-deficient, antigen-activated T cells accumulated higher levels of the proapoptotic BH3-only family member Bim, particularly the most toxic isoform, Bim(S) [20].

Physical interactions of TRAF1

  • TRAF family proteins are signal-transducing adapter proteins that interact with the cytosolic domains of tumor necrosis factor (TNF) family receptors [12].
  • A novel member of the TRAF family of putative signal transducing proteins binds to the cytosolic domain of CD40 [21].
  • The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation [22].
  • The TRAF-binding domain of CD30 was mapped to the COOH-terminal 36 amino acid residues, which contained two independent binding sites [23].
  • We also inducibly expressed in B cells a transfected "dominant-negative" TRAF6 molecule which contains only the C-terminal TRAF-binding domain of TRAF6 [24].

Enzymatic interactions of TRAF1


Regulatory relationships of TRAF1

  • Accordingly, TRAF1 inhibited CD40-dependent but not TNF-R1-dependent NF-kappaB activation [26].
  • These data identify TRAF1 as a specific target of caspases activated during TNF- and Fas-induced apoptosis and illustrate differences in the repertoire of protease substrates cleaved during activation of different apoptotic pathways [12].
  • The ERK1/2 pathway did not appear to be involved in up-regulating TRAF1 and TRAF5 mRNAs in THP1 cells [27].
  • Moreover, cotransfection of a dominant-negative Raf-1 (Raf-C4) significantly reduced PMA-stimulated TRAF1 promoter activity whereas transfection of dominant-negative Ras or treatment with Ras inhibitors had minimal to no effect on TRAF1 induction suggesting dependence on Raf, but not Ras, activation [19].
  • Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase [28].

Other interactions of TRAF1

  • 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 [29].
  • CD40 is a member of the tumor necrosis factor receptor family that mediates a number of important signaling events in B-lymphocytes and some other types of cells through interaction of its cytoplasmic (ct) domain with tumor necrosis factor receptor-associated factor (TRAF) proteins [30].
  • Significant enhancement of TNF receptor-1 (CD120a)- and, to a lesser extent, Fas (CD95)-mediated apoptosis was observed when overexpressing the C-terminal TRAF1 fragment in HEK293T and HT1080 cells [12].
  • Overexpression of TRAF1, however, had no effect on the interaction of TRADD and TRAF2, known to be important for tumor necrosis factor receptor 1 (TNF-R1)-mediated NF-kappaB activation [26].
  • Here we show that TRAF1 and TRAF2 interact with A20, a zinc finger protein, whose expression is induced by agents that activate NF-kappaB [22].

Analytical, diagnostic and therapeutic context of TRAF1


  1. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Mosialos, G., Birkenbach, M., Yalamanchili, R., VanArsdale, T., Ware, C., Kieff, E. Cell (1995) [Pubmed]
  2. Tumor necrosis factor receptor-associated factor 1 is overexpressed in Reed-Sternberg cells of Hodgkin's disease and Epstein-Barr virus-transformed lymphoid cells. Dürkop, H., Foss, H.D., Demel, G., Klotzbach, H., Hahn, C., Stein, H. Blood (1999) [Pubmed]
  3. Tumor necrosis factor receptor-associated factor 1 gene overexpression in B-cell chronic lymphocytic leukemia: analysis of NF-kappa B/Rel-regulated inhibitors of apoptosis. Munzert, G., Kirchner, D., Stobbe, H., Bergmann, L., Schmid, R.M., Döhner, H., Heimpel, H. Blood (2002) [Pubmed]
  4. NF-kappaB2 mutation targets TRAF1 to induce lymphomagenesis. Zhang, B., Wang, Z., Li, T., Tsitsikov, E.N., Ding, H.F. Blood (2007) [Pubmed]
  5. Tumor necrosis factor receptor and Fas signaling mechanisms. Wallach, D., Varfolomeev, E.E., Malinin, N.L., Goltsev, Y.V., Kovalenko, A.V., Boldin, M.P. Annu. Rev. Immunol. (1999) [Pubmed]
  6. A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction. Park, Y.C., Ye, H., Hsia, C., Segal, D., Rich, R.L., Liou, H.C., Myszka, D.G., Wu, H. Cell (2000) [Pubmed]
  7. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Rothe, M., Pan, M.G., Henzel, W.J., Ayres, T.M., Goeddel, D.V. Cell (1995) [Pubmed]
  8. TRAF6 is a signal transducer for interleukin-1. Cao, Z., Xiong, J., Takeuchi, M., Kurama, T., Goeddel, D.V. Nature (1996) [Pubmed]
  9. CD40-mediated regulation of immune responses by TRAF-dependent and TRAF-independent signaling mechanisms. Grammer, A.C., Lipsky, P.E. Adv. Immunol. (2000) [Pubmed]
  10. TRAF5, a novel tumor necrosis factor receptor-associated factor family protein, mediates CD40 signaling. Ishida, T.K., Tojo, T., Aoki, T., Kobayashi, N., Ohishi, T., Watanabe, T., Yamamoto, T., Inoue, J. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  11. Molecular characterization of CD40 signaling intermediates. Werneburg, B.G., Zoog, S.J., Dang, T.T., Kehry, M.R., Crute, J.J. J. Biol. Chem. (2001) [Pubmed]
  12. TRAF1 is a substrate of caspases activated during tumor necrosis factor receptor-alpha-induced apoptosis. Leo, E., Deveraux, Q.L., Buchholtz, C., Welsh, K., Matsuzawa, S., Stennicke, H.R., Salvesen, G.S., Reed, J.C. J. Biol. Chem. (2001) [Pubmed]
  13. Organization of the human tumour necrosis factor receptor-associated factor 1 (TRAF1) gene and mapping to chromosome 9q33-34. Siemienski, K., Peters, N., Scheurich, P., Wajant, H. Gene (1997) [Pubmed]
  14. CD30 induction of human immunodeficiency virus gene transcription is mediated by TRAF2. Tsitsikov, E.N., Wright, D.A., Geha, R.S. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  15. TNFR-associated factor family protein expression in normal tissues and lymphoid malignancies. Zapata, J.M., Krajewska, M., Krajewski, S., Kitada, S., Welsh, K., Monks, A., McCloskey, N., Gordon, J., Kipps, T.J., Gascoyne, R.D., Shabaik, A., Reed, J.C. J. Immunol. (2000) [Pubmed]
  16. 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. Eliopoulos, A.G., Waites, E.R., Blake, S.M., Davies, C., Murray, P., Young, L.S. J. Virol. (2003) [Pubmed]
  17. Expression of the tumor necrosis factor receptor-associated factors (TRAFs) 1 and 2 is a characteristic feature of Hodgkin and Reed-Sternberg cells. Izban, K.F., Ergin, M., Martinez, R.L., Alkan, S. Mod. Pathol. (2000) [Pubmed]
  18. Caspase-cleaved TRAF1 negatively regulates the antiapoptotic signals of TRAF2 during TNF-induced cell death. Jang, H.D., Chung, Y.M., Baik, J.H., Choi, Y.G., Park, I.S., Jung, Y.K., Lee, S.Y. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  19. Regulation of phorbol ester-mediated TRAF1 induction in human colon cancer cells through a PKC/RAF/ERK/NF-kappaB-dependent pathway. Wang, X., Wang, Q., Hu, W., Evers, B.M. Oncogene (2004) [Pubmed]
  20. A critical role for TNF receptor-associated factor 1 and Bim down-regulation in CD8 memory T cell survival. Sabbagh, L., Srokowski, C.C., Pulle, G., Snell, L.M., Sedgmen, B.J., Liu, Y., Tsitsikov, E.N., Watts, T.H. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  21. A novel member of the TRAF family of putative signal transducing proteins binds to the cytosolic domain of CD40. Sato, T., Irie, S., Reed, J.C. FEBS Lett. (1995) [Pubmed]
  22. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Song, H.Y., Rothe, M., Goeddel, D.V. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  23. CD30 contains two binding sites with different specificities for members of the tumor necrosis factor receptor-associated factor family of signal transducing proteins. Gedrich, R.W., Gilfillan, M.C., Duckett, C.S., Van Dongen, J.L., Thompson, C.B. J. Biol. Chem. (1996) [Pubmed]
  24. Characterization of the roles of TNF receptor-associated factor 6 in CD40-mediated B lymphocyte effector functions. Jalukar, S.V., Hostager, B.S., Bishop, G.A. J. Immunol. (2000) [Pubmed]
  25. Caspase-induced inactivation of the anti-apoptotic TRAF1 during Fas ligand-mediated apoptosis. Irmler, M., Steiner, V., Ruegg, C., Wajant, H., Tschopp, J. FEBS Lett. (2000) [Pubmed]
  26. Tumor necrosis factor receptor-associated factor (TRAF) 1 regulates CD40-induced TRAF2-mediated NF-kappaB activation. Fotin-Mleczek, M., Henkler, F., Hausser, A., Glauner, H., Samel, D., Graness, A., Scheurich, P., Mauri, D., Wajant, H. J. Biol. Chem. (2004) [Pubmed]
  27. CD40-mediated signaling in monocytic cells: up-regulation of tumor necrosis factor receptor-associated factor mRNAs and activation of mitogen-activated protein kinase signaling pathways. Pearson, L.L., Castle, B.E., Kehry, M.R. Int. Immunol. (2001) [Pubmed]
  28. Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase. Kim, H.H., Lee, D.E., Shin, J.N., Lee, Y.S., Jeon, Y.M., Chung, C.H., Ni, J., Kwon, B.S., Lee, Z.H. FEBS Lett. (1999) [Pubmed]
  29. Tumor necrosis factor receptor associated factor 2 is a mediator of NF-kappa B activation by latent infection membrane protein 1, the Epstein-Barr virus transforming protein. Kaye, K.M., Devergne, O., Harada, J.N., Izumi, K.M., Yalamanchili, R., Kieff, E., Mosialos, G. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  30. Differential requirements for tumor necrosis factor receptor-associated factor family proteins in CD40-mediated induction of NF-kappaB and Jun N-terminal kinase activation. Leo, E., Welsh, K., Matsuzawa, S., Zapata, J.M., Kitada, S., Mitchell, R.S., Ely, K.R., Reed, J.C. J. Biol. Chem. (1999) [Pubmed]
  31. The human tumor necrosis factor (TNF) receptor-associated factor 1 gene (TRAF1) is up-regulated by cytokines of the TNF ligand family and modulates TNF-induced activation of NF-kappaB and c-Jun N-terminal kinase. Schwenzer, R., Siemienski, K., Liptay, S., Schubert, G., Peters, N., Scheurich, P., Schmid, R.M., Wajant, H. J. Biol. Chem. (1999) [Pubmed]
  32. Cooperation between TNF Receptor-Associated Factors 1 and 2 in CD40 Signaling. Xie, P., Hostager, B.S., Munroe, M.E., Moore, C.R., Bishop, G.A. J. Immunol. (2006) [Pubmed]
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