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Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses

Nature Immunology volume 9, pages 1037–1046 (2008)Cite this article

Abstract

Tumor necrosis factor receptor 1 (TNFR1) and Toll-like receptors (TLRs) regulate immune and inflammatory responses. Here we show that the TNFR1-associated death domain protein (TRADD) is critical in TNFR1, TLR3 and TLR4 signaling. TRADD deficiency abrogated TNF-induced apoptosis, prevented recruitment of the ubiquitin ligase TRAF2 and ubiquitination of the adaptor RIP1 in the TNFR1 signaling complex, and considerably inhibited but did not completely abolish activation of the transcription factor NF-κB and mitogen-activated protein kinases 'downstream' of TNFR1. TRIF-dependent cytokine production induced by the synthetic double-stranded RNA poly(I:C) and lipopolysaccharide was lower in TRADD-deficient mice than in wild-type mice. Moreover, TRADD deficiency inhibited poly(I:C)-mediated RIP1 ubiquitination and activation of NF-κB and mitogen-activated protein kinase signaling in fibroblasts but not in bone marrow macrophages. Thus, TRADD is an essential component of TNFR1 signaling and has a critical but apparently cell type–specific function in TRIF-dependent TLR responses.

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Figure 1: TRADD is required for efficient activation of NF-κB and MAPK downstream of TNFR1.
Figure 2: Impaired germinal center formation and antibody responses in TRADD-deficient mice after immunization with SRBCs.
Figure 3: TRADD is indispensable for TNF-induced apoptosis.
Figure 4: TRADD is important for NF-κB and MAPK activation induced by poly(I:C).
Figure 5: TRADD is important for NF-κB and MAPK activation by LPS.
Figure 6: TRADD acts as a partner of RIP1 and TRIF in TLR3 and TLR4 signaling.

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Acknowledgements

We thank C. Uthoff-Hachenberg and U. Karow for technical assistance; B. Coornaert and N. Hermance for advice on the RIP1 ubiquitination assays; C. Libert (Flanders Institute for Biotechnology) for recombinant TNF; K. Pfeffer (Heinrich-Heine University) for mice lacking TNFR1; S. Akira (Osaka University) for mice lacking MyD88; and D.V. Goeddel (Tularik) for pRK5-TRADD. Supported by the Sixth Research Framework Programme of the European Union (MUGEN (LSHG-CT-2005-005203) and IMDEMI (MRTN-CT-2004-005632)), Deutsche Forschungsgemeinschaft (SFB 670) and the Louis-Jeantet foundation (M.E.).

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Authors and Affiliations

  1. Institute for Genetics, Centre for Molecular Medicine, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, 50674, Germany

    Maria A Ermolaeva, Nikoletta Papadopoulou & Manolis Pasparakis

  2. European Molecular Biology Laboratory Mouse Biology Unit, Monterotondo, 00016, Italy

    Maria A Ermolaeva & Manolis Pasparakis

  3. Department of Biochemistry, University of Lausanne, Epalinges, CH-1066, Switzerland

    Marie-Cécile Michallet & Jürg Tschopp

  4. Institute for Medical Microbiology, Immunology and Hygiene, Medical Center of the University of Cologne, Cologne, 50935, Germany

    Olaf Utermöhlen

  5. Institute of Immunology, Biomedical Sciences Research Center 'Alexander Fleming', Vari, 16672, Greece

    Ksanthi Kranidioti & George Kollias

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  1. Maria A Ermolaeva
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Contributions

M.A.E. generated the TRADD-deficient mice and did most of the experiments; M.-C.M. did the experiments in Figures 1d and 6a,b and Supplementary Figure 3; N.P. contributed to the experiments in Figures 1c,e and 6c; K.K. did the experiments in Figure 2; O.U. supervised the in vivo listeria infection experiments; M.A.E., M.-C.M., N.P., K.K., G.K., J.T. and M.P. designed and analyzed the experiments; and M.A.E. and M.P. wrote the manuscript.

Corresponding author

Correspondence to Manolis Pasparakis.

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Ermolaeva, M., Michallet, MC., Papadopoulou, N. et al. Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses. Nat Immunol 9, 1037–1046 (2008). https://doi.org/10.1038/ni.1638

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