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TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2


Tumour necrosis factor-α (TNF-α) is a proinflammatory mediator that exerts its biological functions by binding two TNF receptors (TNF-RI and TNF-RII), which initiate biological responses by interacting with adaptor and signalling proteins. Among the signalling components that associate with TNF receptors are members of the TNF-R-associated factor (TRAF) family1,2. TRAF2 is required for TNF-α-mediated activation of c-Jun N-terminal kinase (JNK), contributes to activation of NF-κB, and mediates anti-apoptotic signals3, 4. TNF-RI and TNF-RII signalling complexes also contain the anti-apoptotic (‘inhibitor of apoptosis’) molecules c-IAP1 and c-IAP2 (refs 5, 6), which also have RING domain-dependent ubiquitin protein ligase (E3) activity7. The function of IAPs in TNF-R signalling is unknown. Here we show that binding of TNF-α to TNF-RII induces ubiquitination and proteasomal degradation of TRAF2. Although c-IAP1 bound TRAF2 and TRAF1 in vitro, it ubiquitinated only TRAF2. Expression of wild-type c-IAP1, but not an E3-defective mutant, resulted in TRAF2 ubiquitination and degradation. Moreover, E3-defective c-IAP1 prevented TNF-α-induced TRAF2 degradation and inhibited apoptosis. These findings identify a physiologic role for c-IAP1 and define a mechanism by which TNF-RII-regulated ubiquitin protein ligase activity can potentiate TNF-induced apoptosis.

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Figure 1: TNF-α induces ubiquitination and proteasome-mediated degradation of TRAF2.
Figure 2: Ubiquitination of TRAFs by IAPs in vitro.
Figure 3: Ubiquitination and proteasome-mediated degradation of TRAF2 by c-IAP1 in vivo.
Figure 4: c-IAP1-mut blocks TNF-α-induced degradation of TRAF2 and delays apoptosis.
Figure 5: Simple model of TNF-R signalling and regulation by c-IAP1.


  1. Rothe, M., Pan, M. G., Henzel, W. J., Ayres, T. M. & Goeddel, D. V. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83, 1243–1252 (1995).

    CAS  Article  Google Scholar 

  2. Hsu, H., Shu, H. B., Pan, M. G. & Goeddel, D. V. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84, 299–308 (1996).

    CAS  Article  Google Scholar 

  3. Lee, S. Y. et al. TRAF2 is essential for JNK but not NF-κB activation and regulates lymphocyte proliferation and survival. Immunity 7, 703–713 (1997).

    CAS  Article  Google Scholar 

  4. Yeh, W. C. et al. Early lethality, functional NF-κB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 7, 715–725 (1997).

    CAS  Article  Google Scholar 

  5. Shu, H. B., Takeuchi, M. & Goeddel, D. V. The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex. Proc. Natl Acad. Sci. USA 93, 13973–13978 (1996).

    ADS  CAS  Article  Google Scholar 

  6. Chan, F. K., Siegel, M. R. & Lenardo, J. M. Signaling by the TNF receptor superfamily and T cell homeostasis. Immunity 13, 419–422 (2000).

    CAS  Article  Google Scholar 

  7. Yang, Y., Fang, S., Jensen, J. P., Weissman, A. M. & Ashwell, J. D. Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 288, 874–877 (2000).

    ADS  CAS  Article  Google Scholar 

  8. Tschopp, J., Martinon, F. & Hofmann, K. Apoptosis: Silencing the death receptors. Curr. Biol. 9, R381–R384 (1999).

    CAS  Article  Google Scholar 

  9. Van Antwerp, D. J., Martin, S. J., Kafri, T., Green, D. R. & Verma, I. M. Suppression of TNF-α-induced apoptosis by NF-κB. Science 274, 787–789 (1996).

    ADS  CAS  Article  Google Scholar 

  10. Liu, Z. G., Hsu, H., Goeddel, D. V. & Karin, M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-κB activation prevents cell death. Cell 87, 565–576 (1996).

    CAS  Article  Google Scholar 

  11. Deveraux, Q. L. et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 17, 2215–2223 (1998).

    CAS  Article  Google Scholar 

  12. Roy, N., Deveraux, Q. L., Takahashi, R., Salvesen, G. S. & Reed, J. C. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J. 16, 6914–6925 (1997).

    CAS  Article  Google Scholar 

  13. Sarin, A., Conan-Cibotti, M. & Henkart, P. A. Cytotoxic effect of TNF and lymphotoxin on T lymphoblasts. J. Immunol. 155, 3716–3718 (1995).

    CAS  PubMed  Google Scholar 

  14. Zheng, L. et al. Induction of apoptosis in mature T cells by tumour necrosis factor. Nature 377, 348–351 (1995).

    ADS  CAS  Article  Google Scholar 

  15. Duckett, C. S. et al. A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors. EMBO J. 15, 2685–2694 (1996).

    CAS  Article  Google Scholar 

  16. Chan, F. K. & Lenardo, M. J. A crucial role for p80 TNF-R2 in amplifying p60 TNF-R1 apoptosis signals in T lymphocytes. Eur. J. Immunol. 30, 652–660 (2000).

    CAS  Article  Google Scholar 

  17. Arch, R. H., Gedrich, R. W. & Thompson, C. B. Translocation of TRAF proteins regulates apoptotic threshold of cells. Biochem. Biophys. Res. Commun. 272, 936–945 (2000).

    CAS  Article  Google Scholar 

  18. Huang, H. et al. The inhibitor of apoptosis, cIAP2, functions as a ubiquitin-protein ligase and promotes in vitro ubiquitination of caspases-3 and -7. J. Biol. Chem. 275, 26661–26664 (2000).

    CAS  PubMed  Google Scholar 

  19. Rothe, M., Wong, S. C., Henzel, W. J. & Goeddel, D. V. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 78, 681–692 (1994).

    CAS  Article  Google Scholar 

  20. Rothe, M., Sarma, V., Dixit, V. M. & Goeddel, D. V. TRAF2-mediated activation of NF-κB by TNF receptor 2 and CD40. Science 269, 1424–1427 (1995).

    ADS  CAS  Article  Google Scholar 

  21. Reinhard, C., Shamoon, B., Shyamala, V. & Williams, L. T. Tumor necrosis factor α-induced activation of c-jun N-terminal kinase is mediated by TRAF2. EMBO J. 16, 1080–1092 (1997).

    CAS  Article  Google Scholar 

  22. Weiss, T. et al. Enhancement of TNF receptor p60-mediated cytotoxicity by TNF receptor p80: requirement of the TNF receptor-associated factor-2 binding site. J. Immunol. 158, 2398–2404 (1997).

    CAS  PubMed  Google Scholar 

  23. Weiss, T. et al. TNFR80-dependent enhancement of TNFR60-induced cell death is mediated by TNFR-associated factor 2 and is specific for TNFR60. J. Immunol. 161, 3136–3142 (1998).

    CAS  PubMed  Google Scholar 

  24. Erickson, S. L. et al. Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice. Nature 372, 560–563 (1994).

    ADS  CAS  Article  Google Scholar 

  25. Clem, R. J. et al. c-IAP1 is cleaved by caspases to produce a pro-apoptotic C-terminal fragment. J. Biol. Chem. 276, 7602–7608 (2000).

    Article  Google Scholar 

  26. Duckett, C. S. & Thompson, C. B. CD30-dependent degradation of TRAF2: implications for negative regulation of TRAF signaling and the control of cell survival. Genes Dev. 11, 2810–2821 (1997).

    CAS  Article  Google Scholar 

  27. Brown, K. D., Hostager, B. S. & Bishop, G. A. Differential signaling and tumor necrosis factor receptor-associated factor (traf) degradation mediated by CD40 and the epstein-barr virus oncoprotein latent membrane protein 1 (Imp1). J. Exp. Med. 193, 943–954 (2001).

    CAS  Article  Google Scholar 

  28. Peschon, J. J. et al. TNF receptor-deficient mice reveal divergent roles for p55 and p75 in several models of inflammation. J. Immunol. 160, 943–952 (1998).

    CAS  PubMed  Google Scholar 

  29. Lorick, K. L. et al. RING fingers mediate ubiquitin conjugating enzyme (E2)-dependent ubiquitination. Proc. Natl Acad. Sci. USA 96, 11364–11369 (1999).

    ADS  CAS  Article  Google Scholar 

  30. Memon, S. A., Petrak, D., Moreno, M. B. & Zacharchuk, C. M. A simply assay for examining the effect of transiently expressed genes on programmed cell death. J. Immunol. Methods 180, 15–24 (1995).

    CAS  Article  Google Scholar 

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We are grateful to A. Weissman, C. Duckett, and Z. Liu for provision of reagents and reviews of this manuscript. X.L. is a visiting fellow from Bethune International Hospital, China.

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Li, X., Yang, Y. & Ashwell, J. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature 416, 345–347 (2002).

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