NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-α feedforward signaling

Department of Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Cell (Impact Factor: 32.24). 04/2011; 145(1):92-103. DOI: 10.1016/j.cell.2011.02.023
Source: PubMed


Upon DNA damage, ataxia telangiectasia mutated (ATM) kinase triggers multiple events to promote cell survival and facilitate repair. If damage is excessive, ATM stimulates cytokine secretion to alert neighboring cells and apoptosis to eliminate the afflicted cell. ATM augments cell survival by activating nuclear factor (NF)-κB; however, how ATM induces cytokine production and apoptosis remains elusive. Here we uncover a p53-independent mechanism that transmits ATM-driven cytokine and caspase signals upon strong genotoxic damage. Extensive DNA lesions stimulated two sequential NF-κB activation phases, requiring ATM and NEMO/IKK-γ: The first phase induced TNF-α-TNFR1 feedforward signaling, promoting the second phase and driving RIP1 phosphorylation. In turn, RIP1 kinase triggered JNK3/MAPK10-dependent interleukin-8 secretion and FADD-mediated proapoptotic caspase-8 activation. Thus, in the context of excessive DNA damage, ATM employs NEMO and RIP1 kinase through autocrine TNF-α signaling to switch on cytokine production and caspase activation. These results shed light on cell-fate regulation by ATM.

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    • "Activation of cell death is not the only function of RIPK1 kinase. It has also been found to promote synthesis of TNF-a at the mRNA level independent of cell death regulation (Biton and Ashkenazi, 2011; Christofferson et al., 2012; McNamara et al., 2013). This and other cell death-independent proinflammatory activities of RIPK1 kinase are also emerging as potentially clinically relevant targets. "
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    ABSTRACT: RIPK1 and RIPK3, two closely related RIPK family members, have emerged as important regulators of pathologic cell death and inflammation. In the current work, we report that the Bcr-Abl inhibitor and anti-leukemia agent ponatinib is also a first-in-class dual inhibitor of RIPK1 and RIPK3. Ponatinib potently inhibited multiple paradigms of RIPK1- and RIPK3-dependent cell death and inflammatory tumor necrosis factor alpha (TNF-α) gene transcription. We further describe design strategies that utilize the ponatinib scaffold to develop two classes of inhibitors (CS and PN series), each with greatly improved selectivity for RIPK1. In particular, we detail the development of PN10, a highly potent and selective "hybrid" RIPK1 inhibitor, capturing the best properties of two different allosteric RIPK1 inhibitors, ponatinib and necrostatin-1. Finally, we show that RIPK1 inhibitors from both classes are powerful blockers of TNF-induced injury in vivo. Altogether, these findings outline promising candidate molecules and design approaches for targeting RIPK1- and RIPK3-driven inflammatory pathologies. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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    • "Contrary to RIPK1 and RIPK3, MLKL has been reported to specifically transduce TNF-mediated necroptosis, and not apoptosis (Biton and Ashkenazi, 2011; Dondelinger et al., 2013; Murphy et al., 2013; Wang et al., 2008; Wu et al., 2013). In addition , MLKL was shown to act downstream of RIPK1/RIPK3 during necroptosis induction (Chen et al., 2014; Murphy et al., 2013; Sun et al., 2012). "
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    • "RIPK1 is a kinase with several roles in signaling by TNFR1 (Biton and Ashkenazi, 2011; Cusson et al., 2002; Kelliher et al., 1998; Vandenabeele et al., 2010; Zhang et al., 2000), Toll-like receptors (TLRs) (Festjens et al., 2007; Kaiser et al., 2013; Meylan et al., 2004), interferons (Meylan et al., 2004; Thapa et al., 2013), the RIG-I-MAVS pathway (Rajput et al., 2011), and production of IL1a in SHP1-deficient animals (Lukens et al., 2013). Upon activation , it associates with RIPK3 to form a b-amyloid (Li et al., 2012), promoting necroptosis and inflammatory cytokine production , dependent on the pseudokinase, MLKL (Kang et al., 2013; Murphy et al., 2013). "
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