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Beyond Tumor Necrosis Factor Receptor: TRADD Signaling in Toll-Like Receptors

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Beyond Tumor Necrosis Factor Receptor: TRADD Signaling in Toll-Like Receptors Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors Nien-Jung Chen*†‡, Iok In Christine Chio*‡, Wen-Jye Lin*, Gordon Duncan*, Hien Chau*§, David Katz*¶, Huey-Lan Huang*ʈ, Kelly A. Pike*,**, Zhenyue Hao*, Yu-Wen Su*, Kazuo Yamamoto*, Rene´ e F. de Pooter††, Juan Carlos Zu´ n˜ iga-Pflu¨ cker††, Andrew Wakeham*, Wen-Chen Yeh*, and Tak W. Mak*‡‡ *The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2C1; †Institute of Microbiology and Immunology, School of Life Science, National Yang-Ming University, Taipei, Taiwan 112, Republic of China; and ††Department of Immunology, University of Toronto, Sunnybrook and Women’s College Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5 Contributed by Tak W. Mak, July 9, 2008 (sent for review June 24, 2008) Tumor necrosis factor receptor 1-associated death domain protein tory responses in vivo, but also that this molecule is involved in (TRADD) is the core adaptor recruited to TNF receptor 1 (TNFR1) germinal center (GC) formation, T cell costimulation, and TLR upon TNF␣ stimulation. In cells from TRADD-deficient mice, TNF␣- signaling. Our TRADD knockout mice represent a very useful mediated apoptosis and TNF␣-stimulated NF-␬B, JNK, and ERK tool for extending the ever-increasing list of TRADD functions activation are defective. TRADD is also important for germinal in vitro and in vivo. center formation, DR3-mediated costimulation of T cells, and TNF␣- mediated inflammatory responses in vivo. TRADD deficiency does Results not enhance IFN␥-induced signaling. Importantly, TRADD has a TRADD Is Indispensable for TNF␣-Mediated Cell Death. To dissect the novel role in TLR3 and TLR4 signaling. TRADD participates in the role of TRADD in TNF␣-induced signaling, we generated E14.5 TLR4 complex formed upon LPS stimulation, and TRADD-deficient mouse embryonic fibroblast cells (MEFs) from traddWT/WT and macrophages show impaired cytokine production in response to traddKO/KO mice (supporting information (SI) Figs. S1 and S2), TLR ligands in vitro. Thus, TRADD is a multifunctional protein treated them with TNF␣ plus cycloheximide (CHX) for 24 h, and crucial both for TNFR1 signaling and other signaling pathways assessed cell death by 7-AAD staining and flow cytometry. More relevant to immune responses. than 70% of traddWT/WT MEFs underwent apoptosis after stimulation with TNF␣ plus CHX (Fig. 1 A and B). In contrast, TNF ͉ innate immunity traddKO/KO MEFs were completely resistant to TNF␣-induced cell death under the same conditions. MEFs of both genotypes umor necrosis factor alpha (TNF␣) is a pleiotropic cytokine showed equivalent sensitivity to other cell-death-inducing involved in a broad range of biological activities, including agents, including sorbitol, etoposide, doxorubicin, anisomycin, T and UV irradiation (data not shown). Similarly, TRADD defi- inflammation and cell differentiation, survival, and death (1). ϩ TNF␣ mediates these activities by engaging two distinct cell ciency did not alter the susceptibility of CD4 T cells to surface receptors: TNFR1 and TNFR2. Activation of TNFR1 Fas-mediated activation-induced cell death (10), indicating that leads to the recruitment of the intracellular death domain TRADD plays no role in Fas-mediated apoptosis (data not (DD)-containing adaptor TNFR-associated DD protein shown). Taken together, our results show that TRADD is (TRADD) through a homotypic interaction with DD of TNFR1. indispensable for the cell-death arm of TNFR1 signaling but is On one hand, the recruitment of TRADD can promote the not involved in the death triggered by many other agents. association of the TNFR1 complex with Fas-associated DD TRADD Is Essential for TNF␣-Mediated NF-␬B Activation. NF-␬B (FADD), which induces caspase activation and cell death. On the activation is a key signaling event required for TNF␣-induced other hand, TRADD can also recruit receptor-interacting pro- production of inflammatory cytokines (1–3). We compared NF-␬B tein kinase 1 (RIP1) and TNFR-associated factor-2 (TRAF2), activation in MEFs and bone-marrow-derived macrophages (BM- which trigger NF-␬B activation, leading to cell survival and Macs) (data not shown) obtained from traddWT/WT and traddKO/KO proinflammatory responses (1). mice and found that TNF␣-induced NF-␬B activation could not be TRADD was originally identified in a yeast two-hybrid screen triggered in the absence of TRADD (Fig. 1 C and D); meanwhile, performed to identify TNFR1-interacting proteins (2). Intrigu- LPS or IL-1␤-induced NF-␬B activation remained intact (Fig. 1D). ingly, TRADD is the first adaptor protein identified that binds directly to the DD of TNFR1 but transduces signals resulting in IMMUNOLOGY ␬ either apoptosis or NF- B activation (2–4). Indeed, TRADD Author contributions: N.-J.C., I.I.C.C., J.C.Z.-P., W.-C.Y., and T.W.M. designed research; overexpression in 293T cells activates both apoptotic and cell- N.-J.C., I.I.C.C., W.-J.L., G.D., H.C., D.K., H.-L.H., K.A.P., Z.H., Y.-W.S., K.Y., R.F.d.P., and A.W. survival signaling pathways (2). In addition to TNFR1, TRADD performed research; N.-J.C., I.I.C.C., W.-J.L., G.D., and T.W.M. analyzed data; and N.-J.C., may mediate signaling downstream of the death receptors (and I.I.C.C., and T.W.M. wrote the paper. TNFR superfamily members) DR3 and DR6 (5, 6). As well, The authors declare no conflict of interest. recent TRADD knockdown studies have indicated that TRADD Freely available online through the PNAS open access option. may be involved in signaling mediated by receptors unrelated to ‡N.-J.C. and I.I.C.C. contributed equally to this work. the TNFR superfamily, such as in IFN␥ receptor (7–9). These §Present address: Toronto Western Hospital, Toronto, ON, Canada M5T 2S8. findings give tantalizing hints of the potential breadth of ¶Present address: Ontario Cancer Institute, Toronto, ON, Canada M5G 2C1. TRADD functions. ʈPresent address: Academia Sinica, Taipei 11529, Taiwan. To date, a knockout animal model has yet to be reported for **Present address: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, TRADD, even though this important adaptor was identified ON, Canada M5G 1X5. more than ten years ago. In this study, we generate TRADD ‡‡To whom correspondence should be addressed. E-mail: [email protected]. knockout mice by using conditional gene targeting and show that This article contains supporting information online at www.pnas.org/cgi/content/full/ not only is TRADD indispensable for TNF␣-induced NF-␬B 0806585105/DCSupplemental. activation and apoptosis in vitro and TNF␣-induced inflamma- © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0806585105 PNAS ͉ August 26, 2008 ͉ vol. 105 ͉ no. 34 ͉ 12429–12434 Downloaded by guest on October 2, 2021 Right). These observations corroborate with cytoplasmic signaling events upstream of NF-␬B activation in TNF␣-stimulated trad- dWT/WT and traddKO/KO MEFs and BM-Macs. In contrast to the situation in traddWT/WT cells, TNF␣ treatment failed to induce significant degradation of I␬BintraddKO/KO MEFs (Fig. 2A)or BM-Macs (Fig. 2B). To bolster the above findings, we also evaluated IL-6 production in TNF␣-stimulated traddWT/WT and traddKO/KO MEFs by ELISA. We showed that IL-6 was not induced in the absence of TRADD (Fig. S3b), confirming our real-time RT-PCR results (Fig. S3a Left). In contrast, IL-6 production in response to IL-1␤ and LPS stimulation was unaltered in the absence of TRADD (Fig. 3B). TRADD Is Essential for TNFR1-Mediated MAP Kinase Activation. MAP kinase (MAPK) activation is reportedly involved in transducing TNF␣ signaling (15). We therefore analyzed the effect of TRADD deficiency on TNF␣-induced ERK and JNK activation. Surprisingly, traddKO/KO cells still exhibited some degree of JNK and ERK activation in response to murine TNF␣ stimulation, albeit with altered kinetics (Fig. 2 A and B). To eliminate potential confounding effects because of MAPK activation downstream of TNFR2, we stimulated traddWT/WT and KO/KO ␣ Fig. 1. TRADD is indispensable for TNF␣-induced cell death and TNF␣- tradd cells with human TNF , which is thought to prefer- mediated NF-␬B activation. Primary MEFs from traddWT/WT and traddKO/KO entially activate TNFR1 in murine cells (16). Under these mice were treated for 24 h with TNF␣ alone (10 ng/ml), CHX alone (1–10 conditions, MAPK activation was completely abolished in the ␮g/ml), or TNF␣ plus CHX. Viability was assessed by 7-AAD staining and flow absence of TRADD (Fig. 2C), confirming that TRADD is cytometry. (A) Representative flow cytometric data with 1 ␮g/ml CHX. (B) Bar essential for TNFR1-mediated MAPK activation. graph summary of all flow cytometric data. Results shown are the mean Ϯ Ͻ viability SD of triplicate determinations. **, P 0.01, Student’s t test. For A The Composition of the TNFR1 Complex Is Altered in TNF␣-Stimulated and B, data are representative of at least three independent experiments. (C) TRADD-Deficient Cells. TRADD is believed to be the core adaptor Gel mobility shift assay. MEFs from traddWT/WT and traddKO/KO mice were ␣ ␬ that recruits RIP, TRAF2, and FADD into the TNFR1 complex stimulated with 10 ng/ml TNF for the indicated times, and NF- B activation ␣ was evaluated by EMSA. (D) RelA/p65 translocation. The MEFs in A were in response to TNF stimulation (3, 4). To determine whether subjected to immunofluorescent staining to detect RelA/p65 translocation deletion of TRADD would affect TNFR1 complex formation, into the nucleus. MEFs were also treated with LPS (500 ng/ml) or IL-1␤ (10 we treated traddWT/WT and traddKO/KO MEFs with TNF␣ and ng/ml), and RelA/p65 translocation was assessed.
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