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      Many stimuli pull the necrotic trigger, an overview

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          Abstract

          The lab of Jürg Tschopp was the first to report on the crucial role of receptor-interacting protein kinase 1 (RIPK1) in caspase-independent cell death. Because of this pioneer finding, regulated necrosis and in particular RIPK1/RIPK3 kinase-mediated necrosis, referred to as necroptosis, has become an intensively studied form of regulated cell death. Although necrosis was identified initially as a backup cell death program when apoptosis is blocked, it is now recognized as a cellular defense mechanism against viral infections and as being critically involved in ischemia-reperfusion damage. The observation that RIPK3 ablation rescues embryonic lethality in mice deficient in caspase-8 or Fas-associated-protein-via-a-death-domain demonstrates the crucial role of this apoptotic platform in the negative control of necroptosis during development. Here, we review and discuss commonalities and differences of the increasing list of inducers of regulated necrosis ranging from cytokines, pathogen-associated molecular patterns, to several forms of physicochemical cellular stress. Since the discovery of the crucial role of RIPK1 and RIPK3 in necroptosis, these kinases have become potential therapeutic targets. The availability of new pharmacological inhibitors and transgenic models will allow us to further document the important role of this form of cell death in degenerative, inflammatory and infectious diseases.

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          Most cited references 115

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          Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.

          Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.
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            IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis.

            Inhibitor of apoptosis (IAP) proteins are antiapoptotic regulators that block cell death in response to diverse stimuli. They are expressed at elevated levels in human malignancies and are attractive targets for the development of novel cancer therapeutics. Herein, we demonstrate that small-molecule IAP antagonists bind to select baculovirus IAP repeat (BIR) domains resulting in dramatic induction of auto-ubiquitination activity and rapid proteasomal degradation of c-IAPs. The IAP antagonists also induce cell death that is dependent on TNF signaling and de novo protein biosynthesis. Additionally, the c-IAP proteins were found to function as regulators of NF-kappaB signaling. Through their ubiquitin E3 ligase activities c-IAP1 and c-IAP2 promote proteasomal degradation of NIK, the central ser/thr kinase in the noncanonical NF-kappaB pathway.
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              Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.

              Poly(ADP-ribose) polymerase-1 (PARP-1) protects the genome by functioning in the DNA damage surveillance network. PARP-1 is also a mediator of cell death after ischemia-reperfusion injury, glutamate excitotoxicity, and various inflammatory processes. We show that PARP-1 activation is required for translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and that AIF is necessary for PARP-1-dependent cell death. N-methyl-N'-nitro-N-nitrosoguanidine, H2O2, and N-methyl-d-aspartate induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP-1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP-1-dependent cytotoxicity. These data support a model in which PARP-1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death.
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                Author and article information

                Journal
                Cell Death Differ
                Cell Death Differ
                Cell Death and Differentiation
                Nature Publishing Group
                1350-9047
                1476-5403
                January 2012
                11 November 2011
                1 January 2012
                : 19
                : 1
                : 75-86
                Affiliations
                [1 ]Department for Molecular Biomedical Research, VIB , Zwijnaarde-Ghent, Belgium
                [2 ]Department of Biomedical Molecular Biology, Ghent University , Zwijnaarde-Ghent, Belgium
                Author notes
                [* ]Department for Molecular Biomedical Research, VIB-Ghent University , Technologiepark 927, Zwijnaarde-Ghent, 9052 Belgium. Tel: +32 09 33 13760; Fax: +32 09 33 13609; E-mail: Peter.Vandenabeele@ 123456dmbr.vib-UGent.be
                Article
                cdd2011164
                10.1038/cdd.2011.164
                3252835
                22075985
                Copyright © 2012 Macmillan Publishers Limited

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                Categories
                Review

                Cell biology

                pathogens, cytokines, necroptosis, necrosis

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