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The function of TRADD in signaling through tumor necrosis factor receptor 1 and TRIF-dependent Toll-like receptors

Nature Immunology volume 9, pages 1047–1054 (2008)Cite this article

Abstract

The physiological function of the adaptor protein TRADD remains unclear because of the unavailability of a TRADD-deficient animal model. By generating TRADD-deficient mice, we found here that TRADD serves an important function in tumor necrosis factor receptor 1 (TNFR1) signaling by orchestrating the formation of TNFR1 signaling complexes. TRADD was essential for TNFR1 signaling in mouse embryonic fibroblasts but was partially dispensable in macrophages; abundant expression of the adaptor RIP in macrophages may have allowed some transmission of TNFR1 signals in the absence of TRADD. Although morphologically normal, TRADD-deficient mice were resistant to toxicity induced by TNF, lipopolysaccharide and polyinosinic-polycytidylic acid. TRADD was also required for TRIF-dependent Toll-like receptor signaling in mouse embryonic fibroblasts but not macrophages. Our findings definitively establish the biological function of TRADD in TNF signaling.

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Figure 1: Resistance of Tradd−/− mice to TNF cytotoxicity in vivo.
Figure 2: TNFR1-mediated signaling is abolished in Tradd−/− MEFs.
Figure 3: TRADD is essential for the formation of a functional TNFR1 signaling complex in MEFs.
Figure 4: TRADD contributes to TNF signaling in macrophages.
Figure 5: Resistance of Tradd−/− mice to toxicity resulting from LPS and poly(I:C) in the presence of GalN.
Figure 6: TRADD is involved in TLR3 and TLR4 signaling in MEFs.

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Acknowledgements

We thank W.C. Yeh and T.W. Mak (University of Toronto, Canada) for Traf2−/− MEFs; H. Nakano (Juntento University, Japan) for Traf5−/− and Traf2−/−Traf5−/− MEFs; L. Tessarollo (US National Cancer Institute) for the pLTM260 vector; A. Singer (US National Cancer Institute) for the pKO Scrambler 917 TK vector; and L. Pobezinsky for suggestions. Supported by the Intramural Research Program of Center for Cancer Research (US National Cancer Institute).

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Author notes

  1. Yelena L Pobezinskaya, You-Sun Kim and Swati Choksi: These authors contributed equally to this work.

Authors and Affiliations

  1. Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, 20892, Maryland, USA

    Yelena L Pobezinskaya, You-Sun Kim, Swati Choksi, Michael J Morgan, Tao Li & Zhenggang Liu

  2. Transgenic Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Chengyu Liu

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  1. Yelena L Pobezinskaya
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Correspondence to Zhenggang Liu.

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Pobezinskaya, Y., Kim, YS., Choksi, S. et al. The function of TRADD in signaling through tumor necrosis factor receptor 1 and TRIF-dependent Toll-like receptors. Nat Immunol 9, 1047–1054 (2008). https://doi.org/10.1038/ni.1639

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