The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex

Shu, Hong; Takeuchi, Masahiro; Goeddel, David V.

doi:10.1073/pnas.93.24.13973

Cited by 399 publications

(305 citation statements)

References 40 publications

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“…24,29 Previous work implicates TRAF2 as an adaptor that binds to TNFR1 upon ligation by TNFα and recruits cIAPs into the membrane-proximal signaling complex to promote NF-κB activation. 31,33,41,47 TRAF2 inhibits TNFα-induced apoptosis independent of its role in NF-κB activation. 40,48 TRAF2 also suppresses death-receptor-mediated apoptosis by promoting K48-ubiquitination and proteasomal degradation of activated caspase-8.…”

Section: Discussionmentioning

confidence: 99%

“…24 TRAF2 recruits cIAPs to the TNFα-TNFR1 signaling complex, facilitating NF-κB activation. [30][31][32][33] TRAF2 also supports K48-linked ubiquitination and proteasomal degradation of death-receptor-activated caspase-8, curbing apoptosis. 34 TRAF2 KO mice display embryonic lethality; some survive through birth but have severe developmental and immune deficiencies and die prematurely.…”

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confidence: 99%

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TRAF2 is a biologically important necroptosis suppressor

et al. 2015

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Tumor necrosis factor α (TNFα) triggers necroptotic cell death through an intracellular signaling complex containing receptorinteracting protein kinase (RIPK) 1 and RIPK3, called the necrosome. RIPK1 phosphorylates RIPK3, which phosphorylates the pseudokinase mixed lineage kinase-domain-like (MLKL)-driving its oligomerization and membrane-disrupting necroptotic activity. Here, we show that TNF receptor-associated factor 2 (TRAF2)-previously implicated in apoptosis suppression-also inhibits necroptotic signaling by TNFα. TRAF2 disruption in mouse fibroblasts augmented TNFα-driven necrosome formation and RIPK3-MLKL association, promoting necroptosis. TRAF2 constitutively associated with MLKL, whereas TNFα reversed this via cylindromatosis-dependent TRAF2 deubiquitination. Ectopic interaction of TRAF2 and MLKL required the C-terminal portion but not the N-terminal, RING, or CIM region of TRAF2. Induced TRAF2 knockout (KO) in adult mice caused rapid lethality, in conjunction with increased hepatic necrosome assembly. By contrast, TRAF2 KO on a RIPK3 KO background caused delayed mortality, in concert with elevated intestinal caspase-8 protein and activity. Combined injection of TNFR1-Fc, Fas-Fc and DR5-Fc decoys prevented death upon TRAF2 KO. However, Fas-Fc and DR5-Fc were ineffective, whereas TNFR1-Fc and interferon α receptor (IFNAR1)-Fc were partially protective against lethality upon combined TRAF2 and RIPK3 KO. These results identify TRAF2 as an important biological suppressor of necroptosis in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

TRAF2 is a biologically important necroptosis suppressor

et al. 2015

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“…TNF binding induces receptor aggregation, which results in the recruitment of a number of cytoplasmic signaling proteins to two distinct TNFR complexes (Rothe et al, 1994(Rothe et al, , 1995bHsu et al, 1995Hsu et al, , 1996aShu et al, 1996). One of these molecules is TNF receptor associated factor 2 Figure 1 The mammalian stress-activated MAP kinase modules.…”

Section: Tnf Receptor Associated Factors (Trafs)mentioning

confidence: 99%

From receptors to stress-activated MAP kinases

1999

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The cell signaling pathways that culminate in activation of a family of stress-activated MAP kinases are beginning to be de®ned. Determination of cell life and cell death is known to largely depend on the balance of intrinsic life and death signals within cells. Recently, two representative mammalian stress-activated kinases, the JNK and p38 MAP kinases, have been implicated in determination of cell fate by modifying the life, death and di erentiation signals. However, the molecular mechanisms by which extracellular signals are transmitted from membrane receptors to the most upstream kinases in the JNK and p38 signaling modules are not fully understood. This review will provide an overview of current knowledge of molecular links between in¯amma-tory cyokine receptors and stress-activated MAP kinase cascades.

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“…63 Subsequent studies showed that cIAP1 and cIAP2 are also recruited to activated TNFR1 through TRAF2. 48,64 cIAP1/2 proteins are transcriptionally upregulated by TNF-a and cooperate with TRAFs to inhibit TNF-a-induced apoptosis. 65 Although cIAP1-66 and cIAP2-67 deficient mice had no obvious deficit in TNF-ainduced signaling pathways, ablation of both cIAP1 and cIAP2 showed their essential roles in NF-kB activation downstream of TNFR1.…”

Section: Dr Signaling Is Regulated By Ubiquitinationmentioning

confidence: 99%

Regulation of death receptor signaling by the ubiquitin system

Wertz¹,

Dixit²

2009

Cell Death Differ

109

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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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The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex

Cited by 399 publications

References 40 publications

TRAF2 is a biologically important necroptosis suppressor

TRAF2 is a biologically important necroptosis suppressor

From receptors to stress-activated MAP kinases

Regulation of death receptor signaling by the ubiquitin system

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