TRAF1 Is a Negative Regulator of TNF Signaling:: Enhanced TNF Signaling in TRAF1-Deficient Mice (original) (raw)
Related papers
Cell, 2000
The cell activation, cell survival, and antiapoptotic functions of the TNF receptor superfamily are mostly mediated by the family of TNF receptor-associated fac-TRAF proteins are major mediators for the cell activators (TRAF1-6) (Arch et al., 1998). The TRAF proteins tion, cell survival, and antiapoptotic functions of the are also genetically conserved across other multicellular TNF receptor superfamily. They can be recruited to organisms including Drosophila (Liu et al., 1999), C. eleactivated TNF receptors either by direct interactions gans (Wajant et al., 1998), and Dictyostelium discoideum with the receptors or indirectly via the adaptor protein (Regnier et al., 1995). The downstream effectors of TRAF TRADD. We now report the structure of the TRADDsignaling are transcription factors in the NF-B and AP-1 TRAF2 complex, which is highly distinct from recepfamily (Malinin et al., 1997; Nishitoh et al., 1998; Baud tor-TRAF2 interactions. This interaction is significantly et al., 1999), which can turn on numerous genes involved stronger and we show by an in vivo signaling assay in various aspects of cellular and immune functions. In that TRAF2 signaling is more readily initiated by addition, the activation of NF-B and AP-1 have been TRADD than by direct receptor-TRAF2 interactions. shown to render cells protection from apoptosis via the TRADD is specific for TRAF1 and TRAF2, which entranscription of antiapoptotic genes (Beg and Baltimore, sures the recruitment of cIAPs for the direct inhibition 1996; Minden and Karin, 1997). of caspase activation in the signaling complex. The Both subgroups of the TNF receptor superfamily can stronger affinity and unique specificity of the TRADDrecruit TRAF proteins. Those without death domains TRAF2 interaction are crucial for the suppression of recruit many TRAF family members directly for signal apoptosis and provide a mechanistic basis for the pertransduction (Rothe et al., 1994; Arch et al., 1998). Death turbation of TRAF recruitment in sensitizing cell death receptors related to TNFR1, but not Fas, recruit TRAF2 induction. indirectly via the N-terminal domain of the adaptor protein TRADD (Hsu et al., 1996b). TRADD also contains a Introduction death domain and interacts with the intracellular death domain of TNFR1 via homotypic associations (Hsu et The TNF receptor superfamily consists of more than 20 al., 1995). The death domain of TRADD is multifunctional structurally related type I transmembrane proteins that and capable of recruiting two additional signaling proare specifically activated by the corresponding superteins, FADD and RIP (Hsu et al., 1996a, 1996b). FADD can directly recruit and activate caspase-8, giving rise family of TNF␣-like cytokines, eliciting a wide spectrum to the initiation of apoptosis (Boldin et al., 1996; Muzio of cellular responses including transcriptional gene actiet al., 1996). RIP, on the other hand, reinforces the stimuvation and induction of apoptosis (Smith et al., 1994; lation of gene transcription by activating the NF-B sig-Gravestein and Borst, 1998). Members of this receptor naling pathways (Kelliher et al., 1998). superfamily are widely distributed and play key roles in Even though the establishment of TRAF proteins as many crucial biological activities including lymphoid and common signaling molecules explains the partially overneuronal development, innate and adaptive immunity, lapping cellular effects by members of the TNF receptor and maintenance of homeostasis. Agents that manipusuperfamily, it is not clear whether and how TRAF signallate the signaling of these receptors are being used or ing differs between the two subgroups of receptors and showing promise toward the treatment and prevention whether these differences may effect different biological of many human diseases such as rheumatoid arthritis, functions. The indirect TRAF recruitment by TRADD excoronary heart disease, transplantation rejection, insulin ists in the context of the opposing proapoptotic and antiapoptotic pathways. Targeted gene deletion has implicated TRAF2 as essential for the suppression of the § To whom correspondence should be addressed (e-mail: haowu@ med.cornell.edu). intrinsic apoptotic tendency of the TNFR1 signaling Cell 778 Haridas, V., Darnay, B.G., Natarajan, K., Heller, R., and Aggarwal, B.B. (1998). Overexpression of the p80 TNF receptor leads to TNF-We thank Drs. David Goeddel and Wen-Chen Yeh for technical dependent apoptosis, nuclear factor-kappa B activation, and c-Jun suggestions, Drs. Liang Tong, David Cowburn and John Kuriyan for kinase activation. J. Immunol. 160, 3152-3162. critical discussions, Dr. Tim McGraw for help with iodination and Heller, R.A., Song, K., Fan, N., and Chang, D.J. (1992). The p70 tumor DNA sequencing, Dr. Temple Burling for maintaining the X-ray necrosis factor receptor mediates cytotoxicity. Cell 70, 47-56. equipment and computers, Dr. Craig Ogata for access to the HHMI Hendrickson, W.A. (1991). Determination of macromolecular struc-X4A beamline at NSLS, and Vicki Burkitt for technical assistance. tures from anamalous diffraction of synchrotron radiation. Science This work was supported by NIH (AI47831, H. W.), the Speaker's 254, 51-58. fund (H. W.), the departmental startup fund (H. W.), and an NIH Hendrickson, W.A., Horton, J.R., and LeMaster, D.M. (1990). Seleno-Cancer Center grant to the Huntsman Cancer Institute (CA42014). methionyl proteins produced for analysis by multiwavelength anam-H. W. is a Pew Scholar in the Biomedical Sciences. Y. C. P. is a alous diffraction (MAD): a vehicle for direct determination of three postdoctoral fellow of the Cancer Research Institute. dimensional structure. EMBO J. 9,
Biochemical and Biophysical Research Communications, 1997
stimulated hybridomas (13), and of thymocytes (14). CD30 is present on the surfaces of malignant cells The mechanisms by which CD30 mediates these cellufrom patients with Hodgkin's lymphoma, anaplastic lar processes are unclear. large cell lymphoma, and other lymphomas. The yeast Stimulation of T cells with CD30 ligand or anti-CD30 two hybrid genetic screen method was used to identify antibodies has shown that signaling via CD30 regumolecular effectors which mediate CD30 signalling lates p42 MAPK (15) and NFkB (16,17), as has been events. Clones corresponding to genes coding for shown for other members of the TNF receptor super-TRAF1, TRAF2, and TRAF3 molecules, postulated to be family. In order to identify the cellular effectors mediinvolved in signalling via the TNF and CD40 receptors, ating such signals, we and previous researchers have were isolated. In this report, we show that the CD30 used the yeast two hybrid approach to find partners intracellular tail contains two motifs that bind TRAFs. interacting with the intracellular tail of CD30. One The more amino terminal motif, 558 PHYPEQET 565 , group of signaling molecules isolated using this system binds TRAF2 and 3, while the more carboxyl terminal belonged to the TRAF family of proteins which are motif, 576 MLSVEEEG 583 , binds TRAF1 and 2. We known to mediate TNFR p75 and CD40 signalling (18show that these amino acid motifs are conserved in 22). TRAFs are defined by the presence of a TRAF do-TNFRp75 and CD40 and that sequences in these receptors homologous to TRAF-binding sequences found in main which can be subdivided into a highly conserved CD30 can selectively bind the TRAFs in a predictable C-terminal region and a lesser conserved N-terminal manner. ᭧ 1997 Academic Press region (19). As has been shown for CD40, TRAF 2 can mediate activation of NFkB by CD30 (21,23-25). TRAF5 has also been reported to play a similar role in CD30 signaling (26). TRAF 1 and TRAF3 were also CD30 is a cell surface transmembrane protein which found to interact with the CD30 intracellular tail was originally identified using a monoclonal antibody (13,27) but their function remains to be established. directed against Hodgkin's disease Reed-Sternberg To elucidate the mechanism of interaction between cells (1,2). CD30 is also present on cells from other CD30 and the TRAF signaling effectors, we have used lymphomas such as anaplastic large cell lymphoma and a series of CD30 derived peptides in TRAF binding some non-lymphoid tumors (3,4). However, a direct role experiments to define the specific residues within the or mechanism for CD30 in the development or progres-CD30 intracellular tail that mediate this interaction. sion of these tumors has never been clearly established. We also report that similar binding sites capable of The CD30 protein is structurally homologous to the binding with the same specificity to the TRAF proteins TNF receptor (TNFR) superfamily of cellular receptors, are found in the tails of TNF receptor p75 and CD40. which includes CD40, TNFR p55/p75 and Fas (5,6). These receptors are known to have multiple cellular MATERIALS AND METHODS functions including proliferation, differentiation, and apoptosis (7-10). Consistent with the pleiotropic roles Cells, libraries, and antibodies.
Characterization of immune functions in TRAF4-deficient mice
Immunology, 2008
Tumour necrosis factor receptor-associated factor 4 (TRAF4), a member of the TRAF family of proteins, was originally cloned from metastatic breast cancer, where it was overexpressed. 1-3 Recently, we reported that TRAF4 is commonly overexpressed in human carcinomas. 4 Six TRAFs have been described to date which exert a wide range of biological functions, such as in adaptive and innate immunity, embryonic development, stress responses and bone metabolism. 5-8 They serve as adaptive proteins and mediate signals from the tumour necrosis factor receptor (TNFR) and/or interleukin-1/Toll-like receptor (IL-1R/TLR) families. Reports suggest that TRAF4 could be recruited upon signalling triggered via the p75-NGFR (nerve growth factor receptor), 9 LT-bR (lymphotoxin-b receptor), 10 GITR (glucocorticoidinduced TNFR-related protein) 11 and TLR, 12 and in mitogen-activated protein kinase pathways. 13-15 Studies of TRAF mutants or with TRAF knockout mice clearly demonstrate that most TRAF proteins are strongly implicated in multiple immune functions. In TRAF1-deficient mice, an enhanced proliferation of T cells to T-cell receptor and TNFR stimulation is observed, suggesting that TRAF1 is a negative regulator of signalling in these cells. 16 TRAF2 deficiency leads to splenomegaly, lymphadenopathy, enhanced TNF-induced cell death and increased B-cell proliferation in response to various signals. 17,18 In
I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction
Proceedings of the National Academy of Sciences, 1996
Tumor necrosis factor (TNF) receptorassociated factor (TRAF) proteins associate with and transduce signals from TNF receptor 2, CD40, and presumably other members of the TNF receptor superfamily. TRAF2 is required for CD40-and TNF-mediated activation of the transcription factor NF-#cB. Here we describe the isolation and characterization of a novel TRAF-interacting protein, I-TRAF, that binds to the conserved TRAF-C domain of the three known TRAFs. Overexpression of I-TRAF inhibits TRAF2mediated NF-KB activation signaled by CD40 and both TNF receptors. Thus, I-TRAF appears as a natural regulator ofTRAF function that may act by maintaining TRAFs in a latent state.
The role of the TRAF-interacting protein in proliferation and differentiation
Experimental Dermatology, 2012
Ubiquitination of proteins is a post-translational modification which decides on the cellular fate of the protein. Addition of ubiquitin moieties to proteins is carried out by the sequential action of 3 enzyme: E1-activating enzyme, E2-conjugating enzyme and E3 ubiquitin ligase. The TRAF-interacting protein (TRAIP, TRIP, RNF206) functions as RING-type E3 ubiquitin ligase but its physiological substrates are not yet known. TRAIP was reported to interact with TRAF (tumor necrosis factor (TNF) receptorassociated factors) and the two tumor suppressors CYLD and Syk (spleen tyrosine kinase). Ectopically expressed TRAIP was shown to inhibit nuclear factor-kappa B (NF-κB) signaling. However, recent results suggested a role for TRAIP in biological processes other than NF-κB regulation. Knock-down of TRAIP in human epidermal keratinocytes repressed cellular proliferation and induced a block in the G1/S phase of the cell cycle without affecting NF-κB signaling. TRAIP is necessary for embryonal development since mutations affecting the Drosophila homolog of TRAIP are maternal effect-lethal mutants and TRAIP knockout mice die in utero due to aberrant regulation of cell proliferation and apoptosis. These findings underline the tight link between TRAIP and cell proliferation. In this review, we summarize the data on TRAIP and put them into a larger perspective regarding a role of TRAIP in the control of tissue homeostasis.
Tumor Necrosis Factor (TNF) interacts with two receptors known as TNFR1 and TNFR2. TNFR1 activation may result in either cell proliferation or cell death. TNFR2 activates Nuclear Factor-kappaB (NF-kB) and c-Jun N-terminal kinase (JNK) which lead to transcriptional activation of genes related to cell proliferation and survival. This depends on the binding of TNF Receptor Associated Factor 2 (TRAF2) to the receptor. TNFR2 also induces TRAF2 degradation. In this work we have investigated the structural features of TNFR2 responsible for inducing TRAF2 degradation and have studied the biological consequences of this activity. We show that when TNFR1 and TNFR2 are co-expressed, TRAF2 depletion leads to an enhanced TNFR1 cytotoxicity which correlates with the inhibition of NF-kB. NF-kB activation and TRAF2 degradation depend of different regions of the receptor since TNFR2 mutants at amino acids 343-349 fail to induce TRAF2 degradation and have lost their ability to enhance TNFR1-mediated cell death but are still able to activate NF-kB. Moreover, whereas NF-kB activation requires TRAF2 binding to the receptor, TRAF2 degradation appears independent of TRAF2 binding. Thus, TNFR2 mutants unable to bind TRAF2 are still able to induce its degradation and to enhance TNFR1-mediated cytotoxicity. To test further this receptor crosstalk we have developed a system stably expressing in cells carrying only endogenous TNFR1 the chimeric receptor RANK-TNFR2, formed by the extracellular region of RANK (Receptor activator of NF-kB) and the intracellular region of TNFR2.This has made possible to study independently the signals triggered by TNFR1 and TNFR2. In these cells TNFR1 is selectively activated by soluble TNF (sTNF) while RANK-TNFR2 is selectively activated by RANKL. Treatment of these cells with sTNF and RANKL leads to an enhanced cytotoxicity.
Journal of Biological Chemistry, 1996
The tumor necrosis factor (TNF) receptor-associated factor (TRAF) family of proteins interact with and transduce signals for members of the TNF receptor superfamily. TRAF1, TRAF2, and TRAF3 share a conserved Cterminal TRAF domain. TRAF2 plays a key role in transducing signals for activation of the transcription factor nuclear factor-B (NF-B). We have performed extensive mutational analysis on TRAF2, examining the requirements for NF-B activation, self-association, and interaction with other molecules involved in TNF signaling. Examination of point mutants and TRAF2-TRAF3 chimeric proteins indicates that the N-terminal RING finger and two adjacent zinc fingers of TRAF2 are required for NF-B activation. The two distinct TRAF-N and TRAF-C subdomains of the TRAF domain appear to independently mediate self-association and interaction with TRAF1. Interaction of TRAF2 with TNF-R2 and TRADD requires sequences at the C terminus of the TRAF-C domain, whereas interaction with the protein kinase receptor-interacting protein V(RIP) occurs via sequences at the N terminus of the TRAF-C domain. Thus, distinct domains of TRAF2 are involved in recruitment and signaling functions.