Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors

Abstract

Tumor necrosis factor receptor 1-associated death domain protein (TRADD) is the core adaptor recruited to TNF receptor 1 (TNFR1) upon TNF␣ stimulation. In cells from TRADD-deficient mice, TNF␣-mediated apoptosis and TNF␣-stimulated NF-B, JNK, and ERK activation are defective. TRADD is also important for germinal center formation, DR3-mediated costimulation of T cells, and TNF␣-mediated inflammatory responses in vivo. TRADD deficiency does not enhance IFN␥-induced signaling. Importantly, TRADD has a novel role in TLR3 and TLR4 signaling. TRADD participates in the TLR4 complex formed upon LPS stimulation, and TRADD-deficient macrophages show impaired cytokine production in response to TLR ligands in vitro. Thus, TRADD is a multifunctional protein crucial both for TNFR1 signaling and other signaling pathways relevant to immune responses. TNF ͉ innate immunityT umor necrosis factor alpha (TNF␣) is a pleiotropic cytokine involved in a broad range of biological activities, including inflammation and cell differentiation, survival, and death (1). TNF␣ mediates these activities by engaging two distinct cell surface receptors: TNFR1 and TNFR2. Activation of TNFR1 leads to the recruitment of the intracellular death domain (DD)-containing adaptor TNFR-associated DD protein (TRADD) through a homotypic interaction with DD of TNFR1. On one hand, the recruitment of TRADD can promote the association of the TNFR1 complex with Fas-associated DD (FADD), which induces caspase activation and cell death. On the other hand, TRADD can also recruit receptor-interacting protein kinase 1 (RIP1) and TNFR-associated factor-2 (TRAF2), which trigger NF-B activation, leading to cell survival and proinflammatory responses (1).TRADD was originally identified in a yeast two-hybrid screen performed to identify TNFR1-interacting proteins (2). Intriguingly, TRADD is the first adaptor protein identified that binds directly to the DD of TNFR1 but transduces signals resulting in either apoptosis or NF-B activation (2-4). Indeed, TRADD overexpression in 293T cells activates both apoptotic and cellsurvival signaling pathways (2). In addition to TNFR1, TRADD may mediate signaling downstream of the death receptors (and TNFR superfamily members) DR3 and DR6 (5, 6). As well, recent TRADD knockdown studies have indicated that TRADD may be involved in signaling mediated by receptors unrelated to the TNFR superfamily, such as in IFN␥ receptor (7-9). These findings give tantalizing hints of the potential breadth of TRADD functions.To date, a knockout animal model has yet to be reported for TRADD, even though this important adaptor was identified more than ten years ago. In this study, we generate TRADD knockout mice by using conditional gene targeting and show that not only is TRADD indispensable for TNF␣-induced NF-B activation and apoptosis in vitro and TNF␣-induced inflammatory responses in vivo, but also that this molecule is involved in germinal center (GC) formation, T cell costimulation, and TLR signaling. Our TRADD knockout mice represent a very useful t...

TNFα-induced noncanonical NF-κB activation is attenuated by RIP1 through stabilization of TRAF2

“…Because it has a strong affinity for RIP1, TRADD enables the efficient recruitment RIP1 to the TNFR1 receptor complex (Ermolaeva et al, 2008;Pobezinskaya et al, 2008). However, in the absence of TRADD, RIP1 maintains a weak interaction with TNFR1, suggesting that there is also a direct interaction between 653 RIP1 attenuates noncanonical NF-B RIP1 and TNFR1 (Chen et al, 2008;Ermolaeva et al, 2008;Pobezinskaya et al, 2008). Our data here show that loss of this interaction (through a RIP1 deficiency) permits greater TRADD recruitment to TNFR1.…”

Viral Cell Death Inhibitor MC159 Enhances Innate Immunity against Vaccinia Virus Infection

“…Interestingly, we found that MC159 enhanced the binding between RIP1 and TRADD, two essential adaptors for NF-B activation, by multiple TLRs and TNF receptors (9,17,38). We propose that enhanced interaction between RIP1 and TRADD might underlie the mechanism by which MC159 promotes NF-B signaling by innate immune receptors.…”

“…5A, compare panels b and d). The adaptor proteins TRADD (9,17,38) for multiple receptors, including TNF receptor 1 (TNFR-1) and TLR4. We therefore tested whether MC159 might enhance NF-B activation through TRADD and RIP1.…”

Inhibitor of Apoptosis (IAP) Proteins-Modulators of Cell Death and Inflammation

“…This mechanism of Complex-I assembly is well established for some cell types, and the molecular interactions between TRADD, TRAF2, and cIAPs have been revealed by crystallography, as depicted schematically in Figure 6. It is worth remarking, however, that neither TRADD nor RIPK1 are essential components for Complex-I-mediated activation of NF-kB in all cells (Chen et al 2008;Ermolaeva et al 2008;Pobezinskaya et al 2008;Wong et al 2010). In stark contrast, cIAPs are indispensable for TNF-induced activation of NF-kB in all cell types tested so far Varfolomeev et al 2008;Haas et al 2009).…”