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

Ermolaeva, Maria A.; Michallet, M; Papadopoulou, Nikoletta; Utermöhlen, Olaf; Kranidioti, Ksanthi; Kollias, George; Tschopp, Jürg; Pasparakis, Manolis

doi:10.1038/ni.1638

Cited by 247 publications

(214 citation statements)

References 39 publications

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“…Indeed, in recent studies in which TRADD À/À MEFs failed to activate NF-kB in response to TNF, TRADD À/À bone marrow-derived macrophages (BMDM) did so to the same extent as WT BMDMs. 35,36 This implies that the signalling platform assembled on TNFR1 is more plastic than previously thought, and that the function of certain molecules in this complex is interchangeable.…”

Section: Discussionmentioning

confidence: 66%

RIPK1 is not essential for TNFR1-induced activation of NF-κB

et al. 2009

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On TNF binding, receptor-interacting protein kinase 1 (RIPK1) is recruited to the cytoplasmic domain of TNFR1, at which it becomes ubiquitylated and serves as a platform for recruitment and activation of NEMO/IKK1/IKK2 and TAK1/TAB2. RIPK1 is commonly thought to be required for the activation of canonical NF-jB and for inhibition TNFR1-induced apoptosis. RIPK1 has, however, also been reported to be essential for TNFR1-induced apoptosis when cIAPs are depleted. To determine the role of RIPK1 in TNF/IAP antagonist-induced death, we compared wild type (WT) and RIPK1 À/À mouse embryonic fibroblasts (MEFs) treated with these compounds. On being treated with TNF plus IAP antagonist, RIPK1 À/À MEFs survived, unlike WT MEFs, demonstrating a killing activity of RIPK1. Surprisingly, however, on being treated with TNF alone, RIPK1 À/À MEFs activated canonical NF-jB and did not die. Furthermore, several cell types from E18 RIPK1 À/À embryos seem to activate NF-jB in response to TNF. These data indicate that models proposing that RIPK1 is essential for TNFR1 to activate canonical NF-jB are incorrect. Signalling from TNFR1 in response to TNF results in the recruitment and assembly of a membrane-associated complex (complex I), which contains TRADD, RIPK1, TRAF2, cIAP1 and cIAP2. All of these components are thought to be required for the activation of NF-kB in response to TNF. 1 TNFR1 bears a cytoplasmic death domain (DD) and can also transmit apoptotic signals indirectly via TRADD. 2 However, most cells do not die when exposed to TNF, but only succumb when NF-kB signalling is blocked, for example, by deletion of p65 NF-kB (RelA), over-expression of a mutant IkBa, or treatment with the translation inhibitor cycloheximide (CHX). [3][4][5] An essential role for RIPK1 in TNF-induced NF-kB activation has been inferred from overexpression, knockdown and knockout (KO) studies. For example, overexpression of RIPK1-induced NF-kB activation, 6,7 a RIPK1 mutant Jurkat T cell line was deficient in NF-kB activation, 7,8 and extracts from v-ABL-transformed RIPK1 À/À B cells showed no binding to NF-kB probes in electrophoretic mobility shift assays. 4 It is believed that on TNFR1 ligation, RIPK1 is K63 ubiquitylated by TRAF2, 9 which provides a platform for NEMO (IKKg) to bind and allows TAB2/TAB3/TAK1 recruitment. TAK1 becomes ubiquitylated, and subsequently activates IKK2 in a phosphorylation-dependent manner. IKK2 in turn phosphorylates IkBa, which is K48 ubiquitylated and degraded. Degradation of IkBa allows cytoplasmic NF-kB dimers to translocate to the nucleus and transactivate pro-survival proteins such as cFLIP L. 10,11 In this model, by activating NF-kB, RIPK1 shows a pro-survival function.However, it has recently been shown that when cells are treated with an IAP antagonist in addition to TNF, reducing RIPK1 levels using shRNA prevents them from dying. 12 Therefore, in this case RIPK1 seems to have a pro-apoptotic function. To determine the effect of the complete absence of RIPK1 in TNFR1 cell death pathways, we generated mouse em...

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Section: Discussionmentioning

confidence: 66%

RIPK1 is not essential for TNFR1-induced activation of NF-κB

et al. 2009

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“…Along the same line, the enhancement of TLR3-triggered apoptosis when TRADD is depleted could be explained by the involvement of this adapter in the recruitment of TRAF2 to RIP1, as recently suggested for TNFRI. 30 Indeed, TRADD was shown to be required for RIP1 ubiquitination and for proper NF-kB and MAP kinase activation in response to TLR3 stimulation. 30 However, the N-Ter portion of TRIF can also bind TRAF2 directly, irrespective of TRADD.…”

Section: Discussionmentioning

confidence: 99%

“…30 Indeed, TRADD was shown to be required for RIP1 ubiquitination and for proper NF-kB and MAP kinase activation in response to TLR3 stimulation. 30 However, the N-Ter portion of TRIF can also bind TRAF2 directly, irrespective of TRADD. 31 Thus, as previously reported for TNFRI, 27 TRADD appears to protect cells from TLR3-triggered apoptosis through a positive regulatory function as regards RIP1 ubiquitination, although the exact mechanism of its action remains to be clarified.…”

Section: Discussionmentioning

confidence: 99%

dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8

et al. 2012

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Toll-like receptor 3 (TLR3) is a pattern-recognition receptor known to initiate an innate immune response when stimulated by double-stranded RNA (dsRNA). Components of TLR3 signaling, including TIR domain-containing adapter inducing IFN-a (TRIF), have been demonstrated to contribute to dsRNA-induced cell death through caspase-8 and receptor interacting protein (RIP)1 in various human cancer cells. We provide here a detailed analysis of the caspase-8 activating machinery triggered in response to Poly(I:C) dsRNA. Engagement of TLR3 by dsRNA in both type I and type II lung cancer cells induces the formation of an atypical caspase-8-containing complex that is devoid of classical death receptors of the TNFR superfamily, but instead is physically associated to TLR3. The recruitment of caspase-8 to TLR3 requires RIP1, and is negatively modulated by cellular inhibitor of apoptosis protein (cIAP)2-TNF receptor-associated factor (TRAF)2-TNFR-associated death domain (TRADD) ubiquitin ligase complex, which regulates RIP1 ubiquitination. Intriguingly, unlike Fas-or TRAILR-dependent death signaling, caspase-8 recruitment and activation within the TLR3 death-signaling complex appears not to be stringently dependent on Fas-associated with death domain (FADD). Our findings uncover a novel aspect of the molecular mechanisms involved during apoptosis induced by the innate immune receptor TLR3 in cancer cells.

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“…TRADD was discovered in 1995 91 but definitive genetic evidence of the role of TRADD in TNFR1-mediated apoptosis was only recently reported. 92,93 TRADD deficiency blocked TNFR1-induced cell death induced by TNF þ CHX in vitro and by TNF þ GalN in vivo, thereby establishing the essential role of TRADD in proapoptotic signaling downstream of DRs. These studies also analyzed the components of Complex 1 recruited to TNFR1 and found that in the absence of TRADD, less RIP1 and no TRAF2 were associated, and that ubiquitination of RIP1 was markedly reduced.…”

Section: Dr Signaling Is Regulated By Ubiquitinationmentioning

confidence: 99%

Regulation of death receptor signaling by the ubiquitin system

Wertz¹,

Dixit²

2009

Cell Death Differ

112

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The study of death receptor (DR) signaling has led to the discovery of new signaling paradigms, including the first example of direct receptor-mediated activation of a protease (caspase-8) that functions as a second messenger to initiate a 'death cascade' of downstream protease activation. More recently, this receptor system has underscored the importance of ubiquitin modification in NF-jB activation. Both degradative lysine 48-linked polyubiquitin and scaffolding lysine 63-linked polyubiquitin have an essential role in signal propagation. Remarkably, a negative feedback process, termed ubiquitin editing, regulates signaling that emanates from certain DRs. Ubiquitin editing is mediated by a complex interplay between the ubiquitination and deubiquitination machinery, resulting in the replacement of signal enhancing lysine 63-linked polyubiquitin with signal extinguishing lysine 48-linked polyubiquitin. The ubiquitination machinery and its regulation in the context of DR signaling are discussed herein. The tumor necrosis factor receptor (TNFR) family is characterized by the presence of a variable number of cysteinerich domains within the extracellular segment and includes receptors known as the death receptors (DRs). The cognate ligands function in concert with the receptors to orchestrate immune responses, generate secondary lymphoid organs, and modulate the survival, proliferation, and differentiation of responding cells. When this axis goes awry, it can contribute to sepsis, cachexia, and autoimmune disorders including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. 1,2 Indeed, therapeutics based on neutralization of tumor necrosis factor-a (TNF-a) have met unparalleled success in the treatment of many autoimmune disorders. Furthermore, there has been a recent groundswell of enthusiasm for exploiting the proapoptotic properties of the DRs for TRAIL/ Apo2 ligand that selectively mediate the demise of tumor cells.There are six TNFR family DRs identified in humans to date: Fas/CD-95, TNFR1, DR3, DR4, DR5, and DR6. They are characterized by the presence of an B80-residue motif within their cytosolic segments dubbed the death domain (DD). 1,2 The integrity of this domain is essential for engaging downstream signaling components that, depending on the cellular context, promote either prosurvival and proinflammatory signaling pathways or promote apoptosis. 1,2 The DD is sixhelical fold that adopts a 'Greek key' topology and mediates homotypic interactions. There are four death-fold motifs: the DD itself, the death effector domain (DED), caspase activation and recruitment domain (CARD), and the Pyrin domain. 3 Although these folds all possess a similar topological configuration, their surface charge is distinct such that specificity of association is dictated by electrostatic interactions. 3 The DRs initiate signaling by recruiting one of two DD-containing platform adaptor molecules: FADD (Fas Associated Death Domain) that generally mediates apoptosis and/or TRADD (TNF Receptor Associated Death Domain)...

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

Cited by 247 publications

References 39 publications

RIPK1 is not essential for TNFR1-induced activation of NF-κB

RIPK1 is not essential for TNFR1-induced activation of NF-κB

dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8

Regulation of death receptor signaling by the ubiquitin system

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