Immunologic Research

, Volume 39, Issue 1–3, pp 22–32

Multiple roles of TRAF3 signaling in lymphocyte function

Article

Abstract

Members of the tumor necrosis factor receptor (TNFR) superfamily employ cytoplasmic adapter proteins called TNF-R associated factors (TRAF) to initiate and regulate signaling pathways. Although many of these receptors associate with TRAF3, it has been unclear how this TRAF functions in immune responses. New information appearing through the use of novel experimental models reveals that TRAF3 can mediate both activating and inhibitory signals, and can participate in regulation of multiple members of the TNFR superfamily. 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.

Keywords

Signal transduction TNFR superfamily TRAF Lymphocyte activation 

References

  1. 1.
    Bishop GA. The multifaceted roles of TRAFs in the regulation of B cell function. Nat Rev Immunol 2004;4:775–86.PubMedCrossRefGoogle Scholar
  2. 2.
    Hu HM, O’Rourke K, Boguski MS, Dixit VM. A novel RING finger protein interacts with the cytoplasmic domain of CD40. J Biol Chem 1994;269:30069–72.PubMedGoogle Scholar
  3. 3.
    Cheng G, Cleary AM, Ye Z, Hong DI, Lederman S, Baltimore D. Involvement of CRAF1, a relative of TRAF, in CD40 signaling. Science 1995;267:1494–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Sato T, Irie S, Reed JC. A novel member of the TRAF family of putative signal transducing proteins binds to the cytosolic domain of CD40. FEBS Lett 1995;358:113–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Ansieau S, Scheffrahn I, Mosialos G, Brand H, Duyster J, Kaye K, Harada J, Dougall B, Hübinger G, Kieff E, Herrmann F, Leutz A, Gruss H. TRAF-1, TRAF-2 and TRAF-3 interact in vivo with the CD30 cytoplasmic domain: TRAF-2 mediates CD30-induced NF-kB activation. Proc Natl Acad Sci (USA) 1996;93:14053–8.CrossRefGoogle Scholar
  6. 6.
    Devernge O, Hatzivassiliou E, Izumi KM, Kaye KM, Kleijnen MF, Kieff E, Mosialos G. Association of TRAF1, TRAF2, and TRAF3 with an EBV LMP1 domain important for B-lymphocyte transformation: role in NF-kB activation. Mol Cell Biol 1996;16:7098–108.Google Scholar
  7. 7.
    Pullen SS, Dang TTA, Crute JJ, Kehry MR. CD40 signaling through TRAFs. Binding site specificity and activation of downstream pathways by distinct TRAFs. J Biol Chem 1999;274:14246–54.PubMedCrossRefGoogle Scholar
  8. 8.
    Haxhinasto SA, Hostager BS, Bishop GA. Cutting Edge: Molecular mechanisms of synergy between CD40 and the BCR: Role for TRAF2 in receptor interaction J Immunol 2002;169:1145–9.PubMedGoogle Scholar
  9. 9.
    Rothe M, Wong SC, Henzel WJ, Goeddel DV. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 1994;78:681–92.PubMedCrossRefGoogle Scholar
  10. 10.
    Munroe ME, Bishop GA. Role of TRAF2 in distinct and overlapping CD40 and TNFR2/CD120b-mediated B lymphocyte activation. J Biol Chem 2004;279:53222–31.PubMedCrossRefGoogle Scholar
  11. 11.
    Xu Y, Cheng G, Baltimore D. Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses. Immunity 1996;5:407–15.PubMedCrossRefGoogle Scholar
  12. 12.
    Yeh W, Shahinian A, Speiser D, Kraunus J, Billia F, Wakeham A, de la Pampa JL, Ferrick D, Hum B, Iscove N, Ohashi P, Rothe M, Goeddel DV, Mak TW. Early lethality, functional NF-kB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 1997;7:715–25.PubMedCrossRefGoogle Scholar
  13. 13.
    Watts TH. TNF/TNFR family members in costimulation of T cell responses. Ann Rev Immunol 2005;23:23–68.CrossRefGoogle Scholar
  14. 14.
    Krajewski S, Zapata JM, Krajewska M, Van Arsdale T, Shabaik A, Gascoyne RD, Reed JC. Immunohistochemical analysis of in vivo patterns of TRAF3 expression, a member of the TNFR-associated family J Immunol 1997;159:5841–52.PubMedGoogle Scholar
  15. 15.
    Arch RH, Gedrich RW, Thompson CB. TRAFs—a family of adapter proteins that regulates life and death. Genes Devel 1998;12:2821–30.PubMedGoogle Scholar
  16. 16.
    Wajant H, Henkler F, Scheurich P. The TRAF family: Scaffold molecules for cytokine receptors, kinases, and their regulators. Cell Signaling 2001;13:389–400.CrossRefGoogle Scholar
  17. 17.
    Akira S. TLR signaling. J Biol Chem 2003;278:38105–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Häcker H, Redecke V, Blagoev B, Kratchmarova I, Hsu L-C, Wang GG, Kamps MP, Raz E, Wagner H, Häcker G, Mann M, Karin M. Specificity in TLR signalling through distinct effector functions of TRAF3 and TRAF6. Nature 2006;439:204–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Oganesyan G, Saha SK, Guo B, He JQ, Shahangian A, Zarnegar B, Perry A, Cheng G. Critical role of TRAF3 in the TLR-dependent and independent antiviral response. Nature 2006;439:208–11.PubMedCrossRefGoogle Scholar
  20. 20.
    Zarember KA, Godowski PJ. Tissue expression of human TLRs and differential regulation of TLR mRNAs in leukocytes in response to microbes, their products, and cytokines J Immunol 2002;168:554–61.PubMedGoogle Scholar
  21. 21.
    Takayama K, Din ZZ, Mukerjee P, Cooke PH, Kirkland TN. Physicochemical properties of the LPS unit that activates B lymphocytes. J Biol Chem 1990;265:14023–9.PubMedGoogle Scholar
  22. 22.
    Bishop GA, Hsing Y, Hostager BS, Jalukar SV, Ramirez LM, Tomai MA. Molecular mechanisms of B lymphocyte activation by the immune response modifier R-848. J Immunol 2000;165:5552–7.PubMedGoogle Scholar
  23. 23.
    Krieg AM, Yi A-K, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman D. CpG motifs in bacterial DNA trigger direct B cell activation. Nature 1995;374:546–50.PubMedCrossRefGoogle Scholar
  24. 24.
    Bishop GA, Ramirez LM, Baccam M, Busch LK, Pederson LK, Tomai MA. The immune response modifier, Resiquimod, mimics CD40-induced B cell activation. Cell Immunol 2001;208:9–17.PubMedCrossRefGoogle Scholar
  25. 25.
    Baker SJ, Reddy EP. Transducers of life and death: TNF receptor superfamily and associated proteins. Oncogene 1996;12:1–9.PubMedGoogle Scholar
  26. 26.
    Ware CF. APRIL and BAFF connect autoimmunity and cancer. J Exp Med 2000;192:F35–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Grammer AC, Swantek JL, McFarland RD, Miura Y, Geppert T, Lipsky PE. TRAF3 signaling mediates activation of p38 and JNK, cytokine secretion, and Ig production following ligation of CD40 on human B cells. J Immunol 1998;161:1183–93.PubMedGoogle Scholar
  28. 28.
    Hostager BS, Bishop GA. Cutting Edge: contrasting roles of TRAF2 and TRAF3 in CD40-mediated B lymphocyte activation. J Immunol 1999;162:6307–11.PubMedGoogle Scholar
  29. 29.
    Hostager BS, Haxhinasto SA, Rowland SR, Bishop GA. TRAF2-deficient B lymphocytes reveal novel roles for TRAF2 in CD40 signaling. J Biol Chem 2003;278:45382–90.PubMedCrossRefGoogle Scholar
  30. 30.
    Xie P, Hostager BS, Bishop GA. Requirement for TRAF3 in signaling by LMP1, but not CD40, in B lymphocytes. J Exp Med 2004;199:661–71.PubMedCrossRefGoogle Scholar
  31. 31.
    Moore C, Bishop GA. Differential regulation of CD40-mediated TRAF degradation in B lymphocytes. J Immunol 2005;175:3780–9.PubMedGoogle Scholar
  32. 32.
    Haxhinasto SA, Bishop GA. A novel interaction between PKD and TRAFs regulates BCR-CD40 synergy. J Immunol 2003;171:4655–62.PubMedGoogle Scholar
  33. 33.
    Haxhinasto SA, Bishop GA. Synergistic B cell activation by CD40 and the BCR. Role of BCR-mediated kinase activation and TRAF regulation. J Biol Chem 2004;279:2575–82.Google Scholar
  34. 34.
    Liao G, Zhang M, Harhaj EW, Sun S-C. Regulation of NIK by TRAF3-induced degradation. J Biol Chem 2004;279:26243–50.PubMedCrossRefGoogle Scholar
  35. 35.
    Hauer J, Püschner S, Ramakrishnan P, Simon U, Bongers M, Federle C, Engelmann H. TRAF3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kB pathway by TRAF-binding TNFRs. Proc Natl Acad Sci (USA) 2005;102:2874–9.CrossRefGoogle Scholar
  36. 36.
    Ha YJ, Lee JR. Role of TRAF3 in the CD40 signaling by production of reactive oxygen species through association with p40phox, a cytosolic subunit of NADPH oxidase. J Immunol 2004;172:231–9.PubMedGoogle Scholar
  37. 37.
    Xu L, Shu H. TRAF3 is associated with BAFF-R and negatively regulates BAFF-R-mediated NF-kB activation and IL-10 production. J Immunol 2002;169:6883–9.PubMedGoogle Scholar
  38. 38.
    Morrison MD, Reiley W, Zhang M, and Sun S-C. An atypical TRAF-binding motif of BAFF receptor mediates induction of the noncanonical NF-kB signaling pathway. J Biol Chem 2005;280:10018–24.PubMedCrossRefGoogle Scholar
  39. 39.
    Duckett CS, Gedrich RW, Gilfillan MC, Thompson CB. Induction of NF-kB by the CD30 receptor is mediated by TRAF1 and TRAF2. Mol Cell Biol 1997;17:1535–42.PubMedGoogle Scholar
  40. 40.
    Hirata H, Takahashi A, Kobayashi S, Yonehara S, Sawai H, Okazaki T, Yamamoto K, Sasada M. Caspases are activated in a branched protease cascade and control distinct downstream processes in Fas-induced apoptosis. J Exp Med 1998;187:587–94.PubMedCrossRefGoogle Scholar
  41. 41.
    Van Arsdale TL, VanArsdale SL, Force WR, Walter BN, Mosialos G, Kieff E, Reed JC, Ware CF. LTb receptor signaling complex: Role of TRAF3 recruitment in cell death and activation of NF-kB. Proc Natl Acad Sci (USA) 1997;94:2460–5.CrossRefGoogle Scholar
  42. 42.
    Chen H, Hutt-Fletcher L, Cao L, Hayward SD. A positive autoregulatory loop of LMP1 expression and STAT activation in epithelial cells latently infected with EBV. J Virol 2003;77:4139–48.PubMedCrossRefGoogle Scholar
  43. 43.
    Rooney IA, Butrovich KD, Glass AA, Borboroglu S, Benedict CA, Whitbeck JC, Cohen GH, Eisenberg RJ, Ware CF. The lymphotoxin-beta receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells. J Biol Chem 2000;275:14307–15.PubMedCrossRefGoogle Scholar
  44. 44.
    Kawamata S, Hori T, Imura A, Takaori-Kondo A, Uchiyama T. Activation of OX40 signal transduction pathways leads to tumor necrosis factor receptor-associated factor (TRAF) 2- and TRAF5-mediated NF-kappaB activation. J Biol Chem 1998;273:5808–14.PubMedCrossRefGoogle Scholar
  45. 45.
    Kim HH, Lee DE, Shin JN, Lee YS, Jeon YM, Chung CH, Ni J, Kwon BS, Lee ZH. Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase. FEBS Lett 1999;443:297–302.PubMedCrossRefGoogle Scholar
  46. 46.
    Sinha SK, Zachariah S, Quiñones HI, Shindo M, Chaudhary PM. Role of TRAF3 and 6 in the activation of the NF-kB and JNK pathways by X-linked ectodermal dysplasia receptor. J Biol Chem 2002;277:44953–61.PubMedCrossRefGoogle Scholar
  47. 47.
    Xie P, Bishop GA. Roles of TRAF3 in signaling to B lymphocytes by CTAR regions 1 and 2 of the EBV-encoded oncoprotein LMP1. J Immunol 2004;173:5546–55.PubMedGoogle Scholar
  48. 48.
    He JQ, Zarnegar B, Oganesyan G, Saha SK, Yamazaki S, Doyle SE, Dempsey PW, Cheng G. Rescue of TRAF3-null mice by p100 NF-kB deficiency. J Exp Med 2006;203:2413–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Force WR, Cheung TC, Ware CF. Dominant negative mutants of TRAF3 reveal an important role for the coiled coil domains in cell death signaling by the lymphotoxin-b receptor. J Biol Chem 1997;272:30835–40.PubMedCrossRefGoogle Scholar
  50. 50.
    He L, Grammer AC, Wu X, Lipsky PE. TRAF3 forms heterotrimers with TRAF2 and modulates its ability to mediate NF-kB activation. J Biol Chem 2004;279:55855–65.PubMedCrossRefGoogle Scholar
  51. 51.
    Aizawa S, Nakano H, Ishida T, Horie R, Nagai M, Ito K, Yagita H, Okumura K, Inoue J, Watanabe T. TRAF5 and TRAF2 are involved in CD30-mediated NF-kB activation. J Biol Chem 1997;272:2042–5.PubMedCrossRefGoogle Scholar
  52. 52.
    Lee ZH, Lee SE, Kwack K, Yeo W, Lee TH, Bae SS, Suh PG, Kim HH. Caspase-mediated cleavage of TRAF3 in FasL-stimulated Jurkat-T cells. J Leukoc Biol 2001;69:490–6.PubMedGoogle Scholar
  53. 53.
    Thorley-Lawson DA. EBV: exploiting the immune system. Nature Rev Immunol 2001;1:75–82.CrossRefGoogle Scholar
  54. 54.
    Bishop GA, Busch LK. Molecular mechanisms of B lymphocyte transformation by Epstein-Barr virus. Microbes Infec 2002;4:853–7.CrossRefGoogle Scholar
  55. 55.
    Bishop GA, Hostager BS. Signaling by CD40 and its mimics in B cell activation. Immunol Res 2001;24:97–109.PubMedCrossRefGoogle Scholar
  56. 56.
    Farrell PJ, Cludts I, Stühler A. Epstein-Barr virus genes and cancer cells. Biomed Pharmacother 1997;51:258–67.PubMedCrossRefGoogle Scholar
  57. 57.
    Pender MP. Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol 2003;24:584–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Brown KD, Hostager BS, Bishop GA. Differential signaling and TRAF degradation by CD40 and the EBV oncoprotein LMP1. J Exp Med 2001;193:943–54.PubMedCrossRefGoogle Scholar
  59. 59.
    Mosialos G, Birkenback M, Yalamanchili R, VanArsdale T, Ware C, Kieff E. The EBV transforming protein LMP1 engages signaling proteins for the TNF-R family. Cell 1995;80:389–99.PubMedCrossRefGoogle Scholar
  60. 60.
    Kaye KM, Devergne O, Harada JN, Izumi KM, Yalamanchili R, Kieff E, Mosialos G. TRAF2 is a mediator of NF-kB activation by LMP1, the EBV transforming protein. Proc Natl Acad Sci (USA) 1996;93:11085–90.CrossRefGoogle Scholar
  61. 61.
    Eliopoulos AG, Blake SM, Floettmann JE, Rowe M, Young LS. EBV-encoded LMP1 activates the JNK pathway through its extreme C terminus via a mechanism involving TRADD and TRAF2. J Virol 1999;73:1023–35.PubMedGoogle Scholar
  62. 62.
    Miller WE, Cheshire JL, Raab-Traub N. Interaction of TRAF signaling proteins with the LMP1 PXQXT motif is essential for induction of EGF receptor expression. Mol Cell Biol 1998;18:2835–2844.PubMedGoogle Scholar
  63. 63.
    Takeuchi M, Rothe M, Goeddel DV. Anatomy of TRAF2. Distinct domains for NF-kB activation and association with TNF signaling proteins. J Biol Chem 1996;271:19935–42.PubMedCrossRefGoogle Scholar
  64. 64.
    Xie P, Hostager BS, Munroe ME, Moore CR, Bishop GA. Cooperation between TRAFs 1 and 2 in CD40 signaling. J Immunol 2006;176:5388–400.PubMedGoogle Scholar
  65. 65.
    Ni C, Welsh K, Leo E, Wu H, Reed JC, Ely KR. Molecular basis for CD40 signaling mediated by TRAF3. Proc Natl Acad Sci (USA) 2000;97:10395–9.CrossRefGoogle Scholar
  66. 66.
    Wu S, Xie P, Welsh K, Li C, Ni C, Zhu X, Reed JC, Satterthwait AC, Bishop GA, Ely KR. LMP1 protein from EBV is a structural decoy in B lymphocytes for binding to TRAF3. J Biol Chem 2005;280:33620–6.PubMedCrossRefGoogle Scholar
  67. 67.
    Saha SK, Pietras EM, He JQ, Kang JR, Liu SY, Oganesyan G, Shahangian A, Zarnegar B, Shiba TL, Wang Y, Cheng G. Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif. Embo J 2006;25:3257–63.PubMedCrossRefGoogle Scholar
  68. 68.
    Xie P, Stunz LL, Larison KD, Yang B, Bishop GA. B cell-specific TRAF3-deficient mice exhibit expanded B cell compartments in secondary lymphoid organs. J Immunol 2006;176:S191–2.Google Scholar
  69. 69.
    Moreno de Alboran I, O’Hagan RC, Gärtner F, Malynn B, Davidson L, RIckert R, Rajewsky K, DePinho RA, Alt FW. Analysis of c-myc function in normal cells via conditional gene-targeted mutation. Immunity 2001;14:45–55.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Department of MicrobiologyThe University of IowaIowa CityUSA
  2. 2.Department of Internal MedicineThe University of IowaIowa CityUSA
  3. 3.Graduate Program in ImmunologyThe University of IowaIowa CityUSA
  4. 4.VA Medical CenterThe University of IowaIowa CityUSA

Personalised recommendations