Wilson NS, Dixit V, Ashkenazi A.. Death receptor signal transducers: nodes of coordination in immune signaling networks. Nat Immunol 10: 348-355

Genentech, Inc., South San Francisco, California, USA.
Nature Immunology (Impact Factor: 20). 05/2009; 10(4):348-55. DOI: 10.1038/ni.1714
Source: PubMed


Death receptors (DRs) are members of the tumor necrosis factor receptor superfamily that possess a cytoplasmic death domain (DD). DRs regulate important operational and homeostatic aspects of the immune system. They transmit signals through apical protein complexes, which are nucleated by the DD adaptors FADD and TRADD, to control cellular outcomes that range from apoptosis to gene activation. FADD and TRADD also nucleate several distal signaling complexes, which mediate cross-talk between distinct DR signaling pathways. Moreover, together with other DR signal transducers, FADD and TRADD participate in functional complexes assembled by certain non-DR immune cell receptors, such as pattern-recognition receptors. Thus, DR signal transducers may provide important nodes of coordination in immune signaling networks.


Available from: Avi Ashkenazi
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    • "The second one, which is less understood and more recently reported, is believed to take place at an earlier stage following TNFR1 activation and is shown to be independent of the NF-kB response (Dondelinger et al., 2013; Legarda-Addison et al., 2009; O'Donnell et al., 2007, 2012; Wang et al., 2008). Interestingly, while the first checkpoint regulates slow apoptosis by inhibiting activation of complex IIa (TRADD-FADD-caspase-8), the second one regulates the contribution of RIPK1 to cell death by either preventing RIPK1 from integrating the apoptotic complex IIb (RIPK1-FADD-casa- pase-8) or by limiting its contribution to the necrosome (RIPK1- RIPK3-MLKL) (Cho et al., 2009; He et al., 2009; Sun et al., 2012; Vanlangenakker et al., 2011; Wang et al., 2008; Wilson et al., 2009; Zhang et al., 2009; Zhao et al., 2012). It has long been thought that IKKa/IKKb inhibits TNF-induced cell death through activation of the NF-kB pathway. "
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    ABSTRACT: TNF is a master pro-inflammatory cytokine. Activation of TNFR1 by TNF can result in both RIPK1-independent apoptosis and RIPK1 kinase-dependent apoptosis or necroptosis. These cell death outcomes are regulated by two distinct checkpoints during TNFR1 signaling. TNF-mediated NF-κB-dependent induction of pro-survival or anti-apoptotic molecules is a well-known late checkpoint in the pathway, protecting cells from RIPK1-independent death. On the other hand, the molecular mechanism regulating the contribution of RIPK1 to cell death is far less understood. We demonstrate here that the IKK complex phosphorylates RIPK1 at TNFR1 complex I and protects cells from RIPK1 kinase-dependent death, independent of its function in NF-κB activation. We provide in vitro and in vivo evidence that inhibition of IKKα/IKKβ or its upstream activators sensitizes cells to death by inducing RIPK1 kinase-dependent apoptosis or necroptosis. We therefore report on an unexpected, NF-κB-independent role for the IKK complex in protecting cells from RIPK1-dependent death downstream of TNFR1.
    Molecular cell 09/2015; DOI:10.1016/j.molcel.2015.07.032 · 14.02 Impact Factor
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    • "The anti-apoptotic effect of TNF-a is caused by engagement of the adaptor protein TNFRSF1A-associated via death domain (TRADD) (Wilson et al., 2009). TRADD can then interact with TNF receptoreassociated factor 2 (TRAF2) which ultimately leads to activation of NF-kB signaling (Walczak, 2011; Wilson et al., 2009). MicroRNAs (miRNAs) are non protein-coding RNAs that modulate gene expression at the post-transcriptional level (Filipowicz et al., 2005). "
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    ABSTRACT: Nuclear Factor kappa B (NF-κB) signaling is frequently deregulated in a variety of cancers and is constitutively active in estrogen receptor negative (ER-) breast cancer subtypes. These molecular subtypes of breast cancer are associated with poor overall survival. We focused on mechanisms of NF-κB regulation by microRNAs (miRNAs), which regulate eukaryotic gene expression at the post-transcriptional level. In a previous genome-wide miRNA screen, we had identified miR-30c-2-3p as one of the strongest negative regulators of NF-κB signaling. Here we have uncovered the underlying molecular mechanisms and its consequences in breast cancer. In vitro results show that miR-30c-2-3p directly targets both TNFRSF1A-associated via death domain (TRADD), an adaptor protein of the TNFR/NF-κB signaling pathway, and the cell cycle protein Cyclin E1 (CCNE1). Ectopic expression of miR-30c-2-3p downregulated essential cytokines IL8, IL6, CXCL1, and reduced cell proliferation as well as invasion in MDA-MB-231 breast cancer cells. RNA interference (RNAi) induced silencing of TRADD phenocopied the effects on invasion and cytokine expression caused by miR-30c-2-3p, while inhibition of CCNE1 phenocopied the effects on cell proliferation. We further confirmed the tumor suppressive role of this miRNA using a dataset of 781 breast tumors, where higher expression was associated with better survival in breast cancer patients. In summary we have elucidated the mechanism by which miR-30c-2-3p negatively regulates NF-κB signaling and cell cycle progression in breast cancer. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
    Molecular Oncology 02/2015; 9(6). DOI:10.1016/j.molonc.2015.01.008 · 5.33 Impact Factor
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    • "TNFR-1 complex II comprises the adaptor FAS-associated death domain protein (FADD), caspase-8, RIPK1 (IIa), and/or RIPK3 (IIb). E3 ubiquitin ligases, including cIAP-1 and -2 and deubiquitinases , including CYLD (cylindromatosis), A20, Cezanne, HOIL-1/HOIP/Sharpin (LUBAC ubiquitin ligase complex), modify the balance between TNFR-1 complex I and complex II [13] [14] [15] leading to either cell survival via activation of nuclear factor-í µí¼…B (NF-í µí¼…B) or alternative cell death signaling pathways. Homodimerization and activation of caspase-8 within either TNFR complex I or II propagate the activation of effector caspases-3, -6, and -7, which then cause cellular destruction by apoptosis without mitochondria participation (known as type I intrinsic pathway). "
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    ABSTRACT: Under stress conditions, cells in living tissue die by apoptosis or necrosis depending on the activation of the key molecules within a dying cell that either transduce cell survival or death signals that actively destroy the sentenced cell. Multiple extracellular (pH, heat, oxidants, and detergents) or intracellular (DNA damage and Ca 2+ overload) stress conditions trigger various types of the nuclear, endoplasmic reticulum (ER), cytoplasmatic, and mitochondrion-centered signaling events that allow cells to preserve the DNA integrity, protein folding, energetic, ionic and redox homeostasis, thus escaping from injury. Along the transition from reversible to irreversible injury, death signaling is highly heterogeneous and damaged cells may engage autophagy, apoptotic, or necrotic cell death programs. Studies on multiple double- and triple- knockout mice identified caspase-8 , flip , and fadd genes as key regulators of embryonic lethality and inflammation. Caspase-8 has a critical role in pro- and antinecrotic signaling pathways leading to the activation of receptor interacting protein kinase 1 (RIPK1), RIPK3, and the mixed kinase domain-like (MLKL) for a convergent execution pathway of necroptosis or regulated necrosis. Here we outline the recent discoveries into how the necrotic cell death execution pathway is engaged in many physiological and pathological outcome based on genetic analysis of knockout mice.
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