The Ripoptosome, a Signaling Platform that Assembles in Response to Genotoxic Stress and Loss of IAPs

Tenev, Tencho; Bianchi, Katiuscia; Darding, Maurice; Broemer, Meike; Langlais, Claudia; Wållberg, Fredrik; Zachariou, Anna; Lopez, Juanita; MacFarlane, Marion; Cain, Kelvin; Meier, Pascal

doi:10.1016/j.molcel.2011.08.005

Cited by 96 publications

(180 citation statements)

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“…48, 49 Yet, we found that despite the efficiency of Tweak-induced c-IAP1/2 depletion in NIKdeficient MEFs, RIP1 and caspase-8 failed to assemble, indicating that TNFα-induced complex IIb formation is a highly regulated process that is primed by c-IAP1/2 depletion but requires the kinase NIK.…”

Section: Discussionmentioning

confidence: 82%

“…Indeed, we showed that (1) Tweak/TNFα or agonist LTβR/TNFα stimulation led to caspase-8 and RIP1 interaction; (2) RIP1 kinase inhibition by Nec-1 inhibits cell death and blocks caspase-8 and RIP1 association; (3) cell death and RIP1/caspase-8 assembly are severely impaired in NIK-deficient MEFs stimulated with Tweak/TNFα A 2-MDa death-inducing complex containing the core components RIP1/FADD/caspase-8, referred as ripoptosome, was reported to form in response to genotoxic stress or to TLR3 activation in some cancer cell lines. 48,49 In both the studies, the authors found that the assembly of the ripoptosome occurred independently of TNFR1 signaling. However, in our experimental settings, a robust activation of NIK in the absence of TNFR1 stimulation could neither promote a NIK-associated caspase-8 activity nor an interaction between RIP1 and caspase-8.…”

Section: Discussionmentioning

confidence: 99%

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NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

et al. 2015

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NF-κB-inducing kinase (NIK) is well-known for its role in promoting p100/NF-κB2 processing into p52, a process defined as the alternative, or non-canonical, NF-κB pathway. Here we reveal an unexpected new role of NIK in TNFR1-mediated RIP1-dependent apoptosis, a consequence of TNFR1 activation observed in c-IAP1/2-depleted conditions. We show that NIK stabilization, obtained by activation of the non-death TNFRs Fn14 or LTβR, is required for TNFα-mediated apoptosis. These apoptotic stimuli trigger the depletion of c-IAP1/2, the phosphorylation of RIP1 and the RIP1 kinase-dependent assembly of the RIP1/FADD/caspase-8 complex.In the absence of NIK, the phosphorylation of RIP1 and the formation of RIP1/FADD/caspase-8 complex are compromised while c-IAP1/2 depletion is unaffected. In vitro kinase assays revealed that recombinant RIP1 is a bona fide substrate of NIK. In vivo, we demonstrated the requirement of NIK pro-death function, but not the processing of its substrate p100 into p52, in a mouse model of TNFR1/LTβR-induced thymus involution. In addition, we also highlight a role for NIK in hepatocyte apoptosis in a mouse model of virus-induced TNFR1/RIP1-dependent liver damage. We conclude that NIK not only contributes to lymphoid organogenesis, inflammation and cell survival but also to TNFR1/RIP1-dependent cell death independently of the alternative NF-κB pathway.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

et al. 2015

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“…Emerging evidence has suggested that apoptosis and necroptosis can be regulated by a newly defined RIP1, FADD and caspase-8 signalling platform termed the 'ripoptosome', which assembles in response to IAP inhibition by genotoxic stress or pharmacological agents ( Figure 5) (Feoktistova et al, 2011;Tenev et al, 2011). Unlike complex II, the ripoptosome does not originate from or require death receptor activation for assembly.…”

Section: Ripoptosome-a Novel Death-regulating Complexmentioning

confidence: 99%

“…However, the depletion of IAPs, that is, during genotoxic stress or Smac-mimetic treatments, derepresses RIP1 and allows its binding to FADD and caspase-8 to form the ripoptosome. The complex subsequently signals to downstream apoptotic and necroptotic pathways depending on the differential regulation of caspase-8 activity by cFLIP (Feoktistova et al, 2011;Tenev et al, 2011). In the absence of cFLIP, the ripoptosome signals to the apoptotic pathway.…”

Section: Ripoptosome-a Novel Death-regulating Complexmentioning

confidence: 99%

“…Furthermore, IAPs can regulate Ripoptosome-dependent induction of apoptosis and necroptosis. In this respect, the recent study by Tenev et al (2011) demonstrated that the loss of cIAPs induced by Smac mimetics can lead to the activation of the necroptotic pathway and sensitisation of cells to TNF-induced death. Since TNF is often produced during cancer-induced inflammation, the use of Smac mimetics may be an excellent strategy to induce cancer cell death by converting the inflammatory signal to a necroptotic or apoptotic signal.…”

Section: Iap Inhibitors and Smac Mimeticsmentioning

confidence: 99%

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New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

2012

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Pronecrotic mixed lineage kinase domain‐like protein expression is a prognostic biomarker in patients with early‐stage resected pancreatic adenocarcinoma

Colbert

Fisher

Hardy

et al. 2013

Cancer

110

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Background Mixed lineage kinase domain-like protein (MLKL) is a necrosome component mediating programmed necrosis that may be an important determinant of cancer cell death. The goal of the current study was to evaluate the prognostic value of MLKL expression in patients with pancreatic adenocarcinoma (PAC). Methods Tissue from 80 patients was collected from a prospectively maintained database of patients with PAC who underwent pancreaticoduodenectomy between January 2000 and October 2008. Immunohistochemistry analysis was performed and scored using an established scoring system. Kaplan-Meier survival curves were generated for recurrence-free survival (RFS) and overall survival (OS) for all patients and for patients receiving adjuvant chemotherapy. MLKL scores were correlated with RFS and OS using univariate and multivariate Cox regression analyses incorporating clinically relevant covariates. Results The median age of the patients was 63 years and 53% were men. Low MLKL expression was associated with decreased OS (6 months vs 17 months; P=.006). In the subset of 59 patients who received adjuvant chemotherapy, low MLKL expression was associated with decreased RFS (5 months vs 15 months; P=.006) and decreased OS (6 months vs 19 months; P<.0001). On multivariate analysis, low MLKL expression was associated with poor OS in all patients (hazards ratio, 4.6 [95% confidence interval, 1.6-13.8]; P=.006) and in patients receiving adjuvant chemotherapy (hazards ratio, 8.1 [95% confidence interval, 2.2-29.2]; P=.002). Conclusions Low expression of MLKL is associated with decreased OS in patients with resected PAC and decreased RFS and OS in the subset of patients with resected PAC who receive adjuvant chemotherapy. The use of this biomarker in patients with PAC may provide important prognostic information.

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The Ripoptosome, a Signaling Platform that Assembles in Response to Genotoxic Stress and Loss of IAPs

Cited by 96 publications

References 1 publication

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

Pronecrotic mixed lineage kinase domain‐like protein expression is a prognostic biomarker in patients with early‐stage resected pancreatic adenocarcinoma

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