TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte proliferation and survival.

TRAF2 is believed to mediate the activation of NF-kappaB and JNK induced by the tumor necrosis factor receptor (TNFR) superfamily, which elicits pleiotropic responses in lymphocytes. We have investigated the physiological roles of TRAF2 in these processes by expressing a lymphocyte-specific dominant negative form of TRAF2, thereby blocking this protein's effector function. We find that the TNFR superfamily signals require TRAF2 for activation of JNK but not NF-kappaB. In addition, we show that TRAF2 induces NF-kappaB-independent antiapoptotic pathways during TNF-induced apoptosis. Inhibition of TRAF2 leads to splenomegaly, lymphadenopathy, and an increased number of B cells. These findings indicate that TRAF2 is involved in the regulation of lymphocyte function and growth in vivo.

[1]  D. Baltimore,et al.  TANK, a co-inducer with TRAF2 of TNF- and CD 40L-mediated NF-kappaB activation. , 1996, Genes & development.

[2]  D. Donner,et al.  Association of a RING finger protein with the cytoplasmic domain of the human type-2 tumour necrosis factor receptor. , 1995, The Biochemical journal.

[3]  D. Vaux,et al.  Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[4]  D. Baltimore,et al.  Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses. , 1996, Immunity.

[5]  David Baltimore,et al.  An Essential Role for NF-κB in Preventing TNF-α-Induced Cell Death , 1996, Science.

[6]  P. Scheurich,et al.  Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)-alpha: induction of TNF receptors on human T cells and TNF-alpha-mediated enhancement of T cell responses. , 1987, Journal of immunology.

[7]  T. Foy,et al.  The expansive role of CD40 and its ligand, gp39, in immunity. , 1994, Seminars in immunology.

[8]  R. Noelle,et al.  CD40 and its ligand in host defense. , 1996, Immunity.

[9]  Mike Rothe,et al.  The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins , 1995, Cell.

[10]  Michael E. Greenberg,et al.  Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis , 1995, Science.

[11]  C. Ware,et al.  The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family , 1995, Cell.

[12]  E. Kieff,et al.  Identification of TRAF6, a Novel Tumor Necrosis Factor Receptor-associated Factor Protein That Mediates Signaling from an Amino-terminal Domain of the CD40 Cytoplasmic Region* , 1996, The Journal of Biological Chemistry.

[13]  J. Banchereau,et al.  The CD40 antigen and its ligand. , 1994, Annual review of immunology.

[14]  W. J. Boyle,et al.  ATAR, a Novel Tumor Necrosis Factor Receptor Family Member, Signals through TRAF2 and TRAF5* , 1997, The Journal of Biological Chemistry.

[15]  D. Goeddel,et al.  A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor , 1994, Cell.

[16]  Terry Farrah,et al.  The TNF receptor superfamily of cellular and viral proteins: Activation, costimulation, and death , 1994, Cell.

[17]  Douglas K. Miller,et al.  The role of the Caspase family of cysteine proteases in apoptosis. , 1997, Seminars in immunology.

[18]  John Calvin Reed,et al.  A novel member of the TRAF family of putative signal transducing proteins binds to the cytosolic domain of CD40 , 1995, FEBS letters.

[19]  D. Wallach,et al.  MAP3K-related kinase involved in NF-KB induction by TNF, CD95 and IL-1 , 1997, Nature.

[20]  P. Leder,et al.  RIP: A novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death , 1995, Cell.

[21]  B. Kwon,et al.  Signals through 4-1BB are costimulatory to previously activated splenic T cells and inhibit activation-induced cell death. , 1997, Journal of immunology.

[22]  C. Thompson,et al.  CD30 Contains Two Binding Sites with Different Specificities for Members of the Tumor Necrosis Factor Receptor-associated Factor Family of Signal Transducing Proteins* , 1996, The Journal of Biological Chemistry.

[23]  L. Tartaglia,et al.  A novel domain within the 55 kd TNF receptor signals cell death , 1993, Cell.

[24]  Marty W. Mayo,et al.  TNF- and Cancer Therapy-Induced Apoptosis: Potentiation by Inhibition of NF-κB , 1996, Science.

[25]  M. Karin.  The Regulation of AP-1 Activity by Mitogen-activated Protein Kinases (*) , 1995, The Journal of Biological Chemistry.

[26]  G. Natoli,et al.  Activation of SAPK/JNK by TNF Receptor 1 Through a Noncytotoxic TRAF2-Dependent Pathway , 1997, Science.

[27]  Soo-Young Lee,et al.  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 , 1997, The Journal of experimental medicine.

[28]  D. Goeddel,et al.  A death-domain-containing receptor that mediates apoptosis , 1996, Nature.

[29]  C. Thompson,et al.  A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors. , 1996, The EMBO journal.

[30]  Soo Young Lee,et al.  A Regulatory Role for TRAF1 in Antigen-induced Apoptosis of  T Cells , 1997, The Journal of experimental medicine.

[31]  J. Tschopp,et al.  TRAMP, a novel apoptosis-mediating receptor with sequence homology to tumor necrosis factor receptor 1 and Fas(Apo-1/CD95). , 1997, Immunity.

[32]  H. Pircher,et al.  T cell tolerance to Mlsa encoded antigens in T cell receptor V beta 8.1 chain transgenic mice. , 1989, The EMBO journal.

[33]  S. Nagata,et al.  Selective apoptosis of CD4+CD8+ thymocytes by the anti-Fas antibody , 1995, The Journal of experimental medicine.

[34]  T. Mak,et al.  Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection , 1993, Cell.

[35]  Seamus J. Martin,et al.  Suppression of TNF-α-Induced Apoptosis by NF-κB , 1996, Science.

[36]  Arul M. Chinnaiyan,et al.  FADD, a novel death domain-containing protein, interacts with the death domain of fas and initiates apoptosis , 1995, Cell.

[37]  Arul M. Chinnaiyan,et al.  The Receptor for the Cytotoxic Ligand TRAIL , 1997, Science.

[38]  T. Mak,et al.  Signal Transduction, Mitotic Catastrophes, and Death in T‐Cell Development , 1994, Immunological reviews.

[39]  D. Goeddel,et al.  TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. , 1996, Immunity.

[40]  D. Goeddel,et al.  TRAF2-mediated activation of NF-kappa B by TNF receptor 2 and CD40 , 1995, Science.

[41]  J. Inoue,et al.  TRAF5, a novel tumor necrosis factor receptor-associated factor family protein, mediates CD40 signaling. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Hong-Bing Shu,et al.  TRADD–TRAF2 and TRADD–FADD Interactions Define Two Distinct TNF Receptor 1 Signal Transduction Pathways , 1996, Cell.

[43]  A. Schievella,et al.  MADD, a Novel Death Domain Protein That Interacts with the Type 1 Tumor Necrosis Factor Receptor and Activates Mitogen-activated Protein Kinase* , 1997, The Journal of Biological Chemistry.

[44]  A. Chinnaiyan,et al.  Signal Transduction by DR3, a Death Domain-Containing Receptor Related to TNFR-1 and CD95 , 1996, Science.

[45]  E. Chen,et al.  Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Michael Karin,et al.  Dissection of TNF Receptor 1 Effector Functions: JNK Activation Is Not Linked to Apoptosis While NF-κB Activation Prevents Cell Death , 1996, Cell.

[47]  M. Lenardo,et al.  Induction of apoptosis in mature T cells by tumour necrosis factor , 1995, Nature.

[48]  J. Camonis,et al.  A Novel Protein That Interacts with the Death Domain of Fas/APO1 Contains a Sequence Motif Related to the Death Domain (*) , 1995, The Journal of Biological Chemistry.

[49]  M. Boguski,et al.  A novel RING finger protein interacts with the cytoplasmic domain of CD40. , 1994, The Journal of biological chemistry.

[50]  S. Nagata,et al.  A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen. , 1993, The Journal of biological chemistry.

[51]  Zhaodan Cao,et al.  TRAF6 is a signal transducer for interleukin-1 , 1996, Nature.

[52]  R. Geha,et al.  Jak3 is associated with CD40 and is critical for CD40 induction of gene expression in B cells. , 1997, Immunity.

[53]  W. Fiers,et al.  Molecular mechanisms of tumor necrosis factor‐induced cytotoxicity , 1994, FEBS letters.

[54]  D. Baltimore,et al.  Involvement of CRAF1, a relative of TRAF, in CD40 signaling , 1995, Science.

[55]  E. Reddy,et al.  Transducers of life and death: TNF receptor superfamily and associated proteins. , 1996, Oncogene.

[56]  David Wallach,et al.  Involvement of MACH, a Novel MORT1/FADD-Interacting Protease, in Fas/APO-1- and TNF Receptor–Induced Cell Death , 1996, Cell.

[57]  H. Pircher,et al.  Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen , 1989, Nature.

[58]  K. Tamai,et al.  Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes , 1996, Nature.

[59]  L. Williams,et al.  Tumor necrosis factor α‐induced activation of c‐jun N‐terminal kinase is mediated by TRAF2 , 1997, The EMBO journal.

[60]  D. Goeddel,et al.  The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation , 1995, Cell.

[61]  S. Lee,et al.  CD30/TNF receptor-associated factor interaction: NF-kappa B activation and binding specificity. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[62]  P. Hargrave,et al.  Localization of binding sites for carboxyl terminal specific anti-rhodopsin monoclonal antibodies using synthetic peptides. , 1984, Biochemistry.

[63]  S. Srinivasula,et al.  In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[64]  Soo-Young Lee,et al.  T cell receptor-dependent cell death of T cell hybridomas mediated by the CD30 cytoplasmic domain in association with tumor necrosis factor receptor-associated factors , 1996, The Journal of experimental medicine.

[65]  P. Basset,et al.  Presence of a New Conserved Domain in CART1, a Novel Member of the Tumor Necrosis Factor Receptor-associated Protein Family, Which Is Expressed in Breast Carcinoma (*) , 1995, The Journal of Biological Chemistry.

[66]  K. Bauer,et al.  Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activates apoptosis and NF-κB , 1996, Current Biology.

[67]  Matthias Mann,et al.  FLICE, A Novel FADD-Homologous ICE/CED-3–like Protease, Is Recruited to the CD95 (Fas/APO-1) Death-Inducing Signaling Complex , 1996, Cell.

[68]  C. Ware,et al.  TRAF5, an Activator of NF-κB and Putative Signal Transducer for the Lymphotoxin-β Receptor* , 1996, The Journal of Biological Chemistry.