cIAPs Block Ripoptosome Formation, a RIP1/Caspase-8 Containing Intracellular Cell Death Complex Differentially Regulated by cFLIP Isoforms

By M. Feoktistova, P. Geserick, B. Kellert, Diana Panayotova Dimitrova, C. Langlais, M. Hupe, K. Cain, M. MacFarlane, G. Häcker, M. Leverkus. Molecules and Cells, 2011

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Summary The intracellular regulation of cell death pathways by cIAPs has been enigmatic. Here we show that loss of cIAPs promotes the spontaneous formation of an intracellular platform that activates either apoptosis or necroptosis. This 2 MDa intracellular complex that we designate “Ripoptosome” is necessary but not sufficient for cell death. It contains RIP1, FADD, caspase-8, caspase-10, and caspase inhibitor cFLIP isoforms. cFLIPL prevents Ripoptosome formation, whereas, intriguingly, cFLIPS promotes Ripoptosome assembly. When cIAPs are absent, caspase activity is the “rheostat” that is controlled by cFLIP isoforms in the Ripoptosome and decides if cell death occurs by RIP3-dependent necroptosis or caspase-dependent apoptosis. RIP1 is the core component of the complex. As exemplified by our studies for TLR3 activation, our data argue that the Ripoptosome critically influences the outcome of membrane-bound receptor triggering. The differential quality of cell death mediated by the Ripoptosome may cause important pathophysiological consequences during inflammatory responses.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0363f986dd7bffb709df646fb5c0fdf298357b1a

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Citations in the corpus

Pattern Recognition Receptors and the Host Cell Death Molecular Machinery (2018, background): “For example, UV irradiation was reported to induce necroptosis via TNF upregulation but also via spontaneous aggregation of RIPK1 and RIPK3, independently of any death receptor ligation (29, 63).”
Toll-like Receptor 3-mediated Necrosis via TRIF, RIP3, and MLKL* (2013, background): “…vationofNF-(cid:1) B (29, 30), partly dependent on RIP1; 2) initiation of apoptosis via Casp8, which is influenced by RIP1 engagement (4, 19); and 3) initiation of programmed necrosis dependent on RIP1 and RIP3 when Casp8 activity is compromised (5, 31).”
Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3–mediated pathway (2011, background): “Although RIP3 RNAi was shown to slightly suppress Ripoptosomemediated necrosis induced by combination of TLR3 agonist and IAP antagonist (26), we here demonstrated that RIP3-deficient primary macrophages were entirely resistant to TLR3-mediated necrosis in the absence of IAP antagonist.”
Cell Death Signaling. (2015, background): “TRIF recruits RIP1 and RIP3 to induce RIP-dependent necrosis (Feoktistova et al. 2011a).”
Crystal Violet Assay for Determining Viability of Cultured Cells. (2016, background): “Alternatively, molecular studies (e.g., overexpression or knockdown) can be performed to more specifically address the nature of cell death (Feoktistova et al. 2011).”
The RIP1/RIP3 Necrosome Forms a Functional Amyloid Signaling Complex Required for Programmed Necrosis (2012, neutral): “Active caspase-8 within the Ripoptosome cleaves and inactivates RIP1 (Chan et al., 2003; Lin et al., 1999) and RIP3 (Feng et al., 2007).”
The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. (2011, result): “Similar results were obtained by Feoktistova et al. (2011) using poly(I:C) (this issue of Molecular Cell).”
DAI complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA (2012, positive): “Whereas DR-induced necroptosis relies on a RHIM-dependent RIP1-RIP3 signaling complex, virus-induced necrosis follows a RIP3 RHIM-dependent pathway that is independent of RIP1 or TRIF (Upton et al., 2008, 2010).”