Necroptosis
Citations
All
Search in:AllTitleAbstractAuthor name
Publications
(35)
Patents
Grants
Pathways
Clinical trials
Publication
Journal: Nature Reviews Molecular Cell Biology
October/27/2010
Abstract
For a long time, apoptosis was considered the sole form of programmed cell death during development, homeostasis and disease, whereas necrosis was regarded as an unregulated and uncontrollable process. Evidence now reveals that necrosis can also occur in a regulated manner. The initiation of programmed necrosis, 'necroptosis', by death receptors (such as tumour necrosis factor receptor 1) requires the kinase activity of receptor-interacting protein 1 (RIP1; also known as RIPK1) and RIP3 (also known as RIPK3), and its execution involves the active disintegration of mitochondrial, lysosomal and plasma membranes. Necroptosis participates in the pathogenesis of diseases, including ischaemic injury, neurodegeneration and viral infection, thereby representing an attractive target for the avoidance of unwarranted cell death.
Pulse
Views:
1
Posts:
No posts
Rating:
Not rated
Publication
Journal: Nature Reviews Molecular Cell Biology
March/25/2014
Abstract
Cell death research was revitalized by the understanding that necrosis can occur in a highly regulated and genetically controlled manner. Although RIPK1 (receptor-interacting protein kinase 1)- and RIPK3-MLKL (mixed lineage kinase domain-like)-mediated necroptosis is the most understood form of regulated necrosis, other examples of this process are emerging, including cell death mechanisms known as parthanatos, oxytosis, ferroptosis, NETosis, pyronecrosis and pyroptosis. Elucidating how these pathways of regulated necrosis are interconnected at the molecular level should enable this process to be therapeutically targeted.
Publication
Journal: Nature Cell Biology
February/25/2014
Abstract
The mixed lineage kinase domain-like protein (MLKL) has recently been identified as a key RIP3 (receptor interacting protein 3) downstream component of tumour necrosis factor (TNF)-induced necroptosis. MLKL is phosphorylated by RIP3 and is recruited to the necrosome through its interaction with RIP3. However, it is still unknown how MLKL mediates TNF-induced necroptosis. Here, we report that MLKL forms a homotrimer through its amino-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced necroptosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL is critical for mediating necroptosis. Importantly, we found that the membrane localization of MLKL is essential for Ca(2+) influx, which is an early event of TNF-induced necroptosis. Furthermore, we identified that TRPM7 (transient receptor potential melastatin related 7) is a MLKL downstream target for the mediation of Ca(2+) influx and TNF-induced necroptosis. Hence, our study reveals a crucial mechanism of MLKL-mediated TNF-induced necroptosis.
Publication
Journal: Science Signaling
June/20/2010
Abstract
Tumor necrosis factor (TNF) is a pleiotropic molecule with a crucial role in cellular stress and inflammation during infection, tissue damage, and cancer. TNF signaling can lead to three distinct outcomes, each of which is initiated by different signaling complexes: the gene induction or survival mode, the apoptosis mode, and the necrosis mode. The kinases receptor-interacting protein 1 (RIP1) and RIP3 are key signaling molecules in necrosis and are regulated by caspases and ubiquitination. Moreover, TNF stimulation induces the formation of a necrosome in which RIP3 is activated and interacts with enzymes that control glycolytic flux and glutaminolysis. The necrosome induces mitochondrial complex I-mediated production of reactive oxygen species (ROS) and cytotoxicity, which suggest a functional link between increased bioenergetics and necrosis. In addition, other effector mechanisms also contribute to TNF-induced necrosis, such as recruitment of NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate) oxidases and subsequent ROS production at the membrane-associated TNF receptor complex I; calcium mobilization; activation of phospholipase A(2), lipoxygenases, and acid sphingomyelinases; and lysosomal destabilization. However, the link between RIP1 and RIP3 and these subcellular events remains to be established. The regulation of RIP1 and RIP3 and their downstream signaling cascades opens new therapeutic avenues for treatment of pathologies associated with cell loss, such as ischemia-reperfusion damage and neurodegeneration, and ways to stimulate alternative immunogenic cell death pathways in cancer.
Publication
Journal: Nature Reviews Immunology
July/29/2015
Abstract
Tumour necrosis factor (TNF) is a pro-inflammatory cytokine that has important roles in mammalian immunity and cellular homeostasis. Deregulation of TNF receptor (TNFR) signalling is associated with many inflammatory disorders, including various types of arthritis and inflammatory bowel disease, and targeting TNF has been an effective therapeutic strategy in these diseases. This Review focuses on the recent advances that have been made in understanding TNFR signalling and the consequences of its deregulation for cellular survival, apoptosis and regulated necrosis. We discuss how TNF-induced survival signals are distinguished from those that lead to cell death. Finally, we provide a brief overview of the role of TNF in inflammatory and autoimmune diseases, and we discuss up-to-date and future treatment strategies for these disorders.
Publication
Journal: Cell Death and Differentiation
March/29/2012
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.
Publication
Journal: Nature Reviews Molecular Cell Biology
December/18/2013
Abstract
Receptor-interacting protein 1 (RIP1) kinase has emerged as a key upstream regulator that controls inflammatory signalling as well as the activation of multiple cell death pathways, including apoptosis and necroptosis. The ability of RIP1 to modulate these key cellular events is tightly controlled by ubiquitylation, deubiquitylation and the interaction of RIP1 with a class of ubiquitin receptors. The modification of RIP1 may thus provide a unique 'ubiquitin code' that determines whether a cell activates nuclear factor-κB (NF-κB) to promote inflammatory signalling or induces cell death by apoptosis or necroptosis. Targeting RIP1 might be a novel therapeutic strategy for the treatment of both acute and chronic human diseases.
Publication
Journal: Nature Communications
March/13/2016
Abstract
RIPK3 and its substrate MLKL are essential for necroptosis, a lytic cell death proposed to cause inflammation via the release of intracellular molecules. Whether and how RIPK3 might drive inflammation in a manner independent of MLKL and cell lysis remains unclear. Here we show that following LPS treatment, or LPS-induced necroptosis, the TLR adaptor protein TRIF and inhibitor of apoptosis proteins (IAPs: X-linked IAP, cellular IAP1 and IAP2) regulate RIPK3 and MLKL ubiquitylation. Hence, when IAPs are absent, LPS triggers RIPK3 to activate caspase-8, promoting apoptosis and NLRP3-caspase-1 activation, independent of RIPK3 kinase activity and MLKL. In contrast, in the absence of both IAPs and caspase-8, RIPK3 kinase activity and MLKL are essential for TLR-induced NLRP3 activation. Consistent with in vitro experiments, interleukin-1 (IL-1)-dependent autoantibody-mediated arthritis is exacerbated in mice lacking IAPs, and is reduced by deletion of RIPK3, but not MLKL. Therefore RIPK3 can promote NLRP3 inflammasome and IL-1β inflammatory responses independent of MLKL and necroptotic cell death.
Publication
Journal: Nature Immunology
September/15/2015
Abstract
Inflammation is a healthy response to infection or danger and should be rapid, specific and terminated once the threat has passed. Inflammatory diseases, where this regulation fails, cause considerable human suffering. Treatments have successfully targeted pro-inflammatory cytokines, such as tumor-necrosis factor (TNF), that directly induce genes encoding inflammatory products. Inflammatory signals, including TNF, may also directly induce caspase-independent cell death (necroptosis), which can also elicit inflammation. Necroptosis was originally defined as being dependent on the kinase RIPK1 but is now known to be dependent on RIPK3 and the pseudo-kinase MLKL. Therefore, RIPK1, RIPK3 and MLKL are potential therapeutic targets. RIPK1 and RIPK3 also directly regulate inflammatory signaling, which complicates interpretation of their function but might alter their therapeutic utility. This Review examines the role of cell death, particularly necroptosis, in inflammation, in the context of recent insights into the roles of the key necroptosis effector molecules RIPK1, RIPK3 and MLKL.
Publication
Journal: Genes and Development
October/28/2013
Abstract
The receptor-interacting protein kinase 3 (RIP3/RIPK3) has emerged as a critical regulator of programmed necrosis/necroptosis, an inflammatory form of cell death with important functions in pathogen-induced and sterile inflammation. RIP3 activation is tightly regulated by phosphorylation, ubiquitination, and caspase-mediated cleavage. These post-translational modifications coordinately regulate the assembly of a macromolecular signaling complex termed the necrosome. Recently, several reports indicate that RIP3 can promote inflammation independent of its pronecrotic activity. Here, we review our current understanding of the mechanisms that drive RIP3-dependent necrosis and its role in different inflammatory diseases.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
November/10/2013
Abstract
Interferons (IFNs) are cytokines with powerful immunomodulatory and antiviral properties, but less is known about how they induce cell death. Here, we show that both type I (α/β) and type II (γ) IFNs induce precipitous receptor-interacting protein (RIP)1/RIP3 kinase-mediated necrosis when the adaptor protein Fas-associated death domain (FADD) is lost or disabled by phosphorylation, or when caspases (e.g., caspase 8) are inactivated. IFN-induced necrosis proceeds via progressive assembly of a RIP1-RIP3 "necrosome" complex that requires Jak1/STAT1-dependent transcription, but does not need the kinase activity of RIP1. Instead, IFNs transcriptionally activate the RNA-responsive protein kinase PKR, which then interacts with RIP1 to initiate necrosome formation and trigger necrosis. Although IFNs are powerful activators of necrosis when FADD is absent, these cytokines are likely not the dominant inducers of RIP kinase-driven embryonic lethality in FADD-deficient mice. We also identify phosphorylation on serine 191 as a mechanism that disables FADD and collaborates with caspase inactivation to allow IFN-activated necrosis. Collectively, these findings outline a mechanism of IFN-induced RIP kinase-dependent necrotic cell death and identify FADD and caspases as negative regulators of this process.
Publication
Journal: Nature Reviews Drug Discovery
July/12/2017
Abstract
The discovery of regulated cell death presents tantalizing possibilities for gaining control over the life-death decisions made by cells in disease. Although apoptosis has been the focus of drug discovery for many years, recent research has identified regulatory mechanisms and signalling pathways for previously unrecognized, regulated necrotic cell death routines. Distinct critical nodes have been characterized for some of these alternative cell death routines, whereas other cell death routines are just beginning to be unravelled. In this Review, we describe forms of regulated necrotic cell death, including necroptosis, the emerging cell death modality of ferroptosis (and the related oxytosis) and the less well comprehended parthanatos and cyclophilin D-mediated necrosis. We focus on small molecules, proteins and pathways that can induce and inhibit these non-apoptotic forms of cell death, and discuss strategies for translating this understanding into new therapeutics for certain disease contexts.
Publication
Journal: Nature Reviews Immunology
June/8/2017
Abstract
Eukaryotic cells can die from physical trauma, which results in necrosis. Alternatively, they can die through programmed cell death upon the stimulation of specific signalling pathways. In this Review, we discuss the role of different cell death pathways in innate immune defence against bacterial and viral infection: apoptosis, necroptosis, pyroptosis and NETosis. We describe the interactions that interweave different programmed cell death pathways, which create complex signalling networks that cross-guard each other in the evolutionary 'arms race' with pathogens. Finally, we describe how the resulting cell corpses - apoptotic bodies, pore-induced intracellular traps (PITs) and neutrophil extracellular traps (NETs) - promote the clearance of infection.
Publication
Journal: Cell
June/22/2017
Abstract
The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. Here, we show that, during necroptosis, MLKL-dependent calcium (Ca2+) influx and phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane preceded loss of PM integrity. Activation of MLKL results in the generation of broken, PM "bubbles" with exposed PS that are released from the surface of the otherwise intact cell. The ESCRT-III machinery is required for formation of these bubbles and acts to sustain survival of the cell when MLKL activation is limited or reversed. Under conditions of necroptotic cell death, ESCRT-III controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT-III, cells undergoing necroptosis can express chemokines and other regulatory molecules and promote antigenic cross-priming of CD8+ T cells.
Pulse
Views:
1
Posts:
No posts
Rating:
Not rated
Publication
Journal: Developmental Cell
September/19/2017
Abstract
Although autophagy controls cell death and survival, underlying mechanisms are poorly understood, and it is unknown whether autophagy affects only whether or not cells die or also controls other aspects of programmed cell death. MAP3K7 is a tumor suppressor gene associated with poor disease-free survival in prostate cancer. Here, we report that Map3k7 deletion in mouse prostate cells sensitizes to cell death by TRAIL (TNF-related apoptosis-inducing ligand). Surprisingly, this death occurs primarily through necroptosis, not apoptosis, due to assembly of the necrosome in association with the autophagy machinery, mediated by p62/SQSTM1 recruitment of RIPK1. The mechanism of cell death switches to apoptosis if p62-dependent recruitment of the necrosome to the autophagy machinery is blocked. These data show that the autophagy machinery can control the mechanism of programmed cell death by serving as a scaffold rather than by degrading cargo.
Publication
Journal: Journal of Biological Chemistry
January/25/2010
Abstract
Ubiquitination and deubiquitination of receptor-interacting protein 1 (RIP1) play an important role in the positive and negative regulation of the tumor necrosis factor alpha (TNFalpha)-induced nuclear factor kappaB (NF-kappaB) activation. Using a combination of functional genomic and proteomic approaches, we have identified ubiquitin-specific peptidase 21 (USP21) as a deubiquitinase for RIP1. USP21 is constitutively associated with RIP1 and deubiquitinates RIP1 in vitro and in vivo. Notably, knockdown of USP21 in HeLa cells enhances TNFalpha-induced RIP1 ubiquitination, IkappaB kinase beta (IKKbeta), and NF-kappaB phosphorylation, inhibitor of NF-kappaB alpha (IkappaB alpha) phosphorylation and ubiquitination, as well as NF-kappaB-dependent gene expression. Therefore, our results demonstrate that USP21 plays an important role in the down-regulation of TNFalpha-induced NF-kappaB activation through deubiquitinating RIP1.
Pulse
Views:
1
Posts:
No posts
Rating:
Not rated
Publication
Journal: Cell Death and Differentiation
April/30/2012
Abstract
Alkylating DNA-damage agents such as N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG) trigger necroptosis, a newly defined form of programmed cell death (PCD) managed by receptor interacting protein kinases. This caspase-independent mode of cell death involves the sequential activation of poly(ADP-ribose) polymerase-1 (PARP-1), calpains, BAX and AIF, which redistributes from mitochondria to the nucleus to promote chromatinolysis. We have previously demonstrated that the BAX-mediated mitochondrial release of AIF is a critical step in MNNG-mediated necroptosis. However, the mechanism regulating BAX activation in this PCD is poorly understood. Employing mouse embryonic knockout cells, we reveal that BID controls BAX activation in AIF-mediated necroptosis. Indeed, BID is a link between calpains and BAX in this mode of cell death. Therefore, even if PARP-1 and calpains are activated after MNNG treatment, BID genetic ablation abolishes both BAX activation and necroptosis. These PCD defects are reversed by reintroducing the BID-wt cDNA into the BID(-/-) cells. We also demonstrate that, after MNNG treatment, BID is directly processed into tBID by calpains. In this way, calpain non-cleavable BID proteins (BID-G70A or BID-Δ68-71) are unable to promote BAX activation and necroptosis. Once processed, tBID localizes in the mitochondria of MNNG-treated cells, where it can facilitate BAX activation and PCD. Altogether, our data reveal that, as in caspase-dependent apoptosis, BH3-only proteins are key regulators of caspase-independent necroptosis.
Publication
Journal: Cell Death and Differentiation
August/2/2015
Abstract
Innate immunity represents the first line of defence against invading pathogens. It consists of an initial inflammatory response that recruits white blood cells to the site of infection in an effort to destroy and eliminate the pathogen. Some pathogens replicate within host cells, and cell death by apoptosis is an important effector mechanism to remove the replication niche for such microbes. However, some microbes have evolved evasive strategies to block apoptosis, and in these cases host cells may employ further countermeasures, including an inflammatory form of cell death know as necroptosis. This review aims to highlight the importance of the RIP kinase family in controlling these various defence strategies. RIP1 is initially discussed as a key component of death receptor signalling and in the context of dictating whether a cell triggers a pathway of pro-inflammatory gene expression or cell death by apoptosis. The molecular and functional interplay of RIP1 and RIP3 is described, especially with respect to mediating necroptosis and as key mediators of inflammation. The function of RIP2, with particular emphasis on its role in NOD signalling, is also explored. Special attention is given to emphasizing the physiological and pathophysiological contexts for these various functions of RIP kinases.
Publication
Journal: Molecular and Cellular Biology
October/6/2011
Abstract
Interferons (IFNs) are cytokines with well-described immunomodulatory and antiviral properties, but less is known about the mechanisms by which they promote cell survival or cell death. Here, we show that IFN-γ induces RIP1 kinase-dependent necroptosis in mammalian cells deficient in NF-κB signaling. Induction of necroptosis by IFN-γ was found to depend on Jak1 and partially on STAT1. We also demonstrate that IFN-γ activates IκB kinase β (IKKβ)-dependent NF-κB to regulate a transcriptional program that protects cells from necroptosis. IFN-γ induced progressive accumulation of reactive oxygen species (ROS) and eventual loss of mitochondrial membrane potential in cells lacking the NF-κB subunit RelA. Whole-genome microarray analyses identified sod2, encoding the antioxidant enzyme manganese superoxide dismutase (MnSOD), as a RelA target and potential antinecroptotic gene. Overexpression of MnSOD inhibited IFN-γ-mediated ROS accumulation and partially rescued RelA-deficient cells from necroptosis, while RNA interference (RNAi)-mediated silencing of sod2 expression increased susceptibility to IFN-γ-induced cell death. Together, these studies demonstrate that NF-κB protects cells from IFN-γ-mediated necroptosis by transcriptionally activating a survival response that quenches ROS to preserve mitochondrial integrity.
Publication
Journal: Cell host & microbe
September/5/2017
Abstract
Influenza A virus (IAV) is an RNA virus that is cytotoxic to most cell types in which it replicates. IAV activates the host kinase RIPK3, which induces cell death via parallel pathways of necroptosis, driven by the pseudokinase MLKL, and apoptosis, dependent on the adaptor proteins RIPK1 and FADD. How IAV activates RIPK3 remains unknown. We report that DAI (ZBP1/DLM-1), previously implicated as a cytoplasmic DNA sensor, is essential for RIPK3 activation by IAV. Upon infection, DAI recognizes IAV genomic RNA, associates with RIPK3, and is required for recruitment of MLKL and RIPK1 to RIPK3. Cells lacking DAI or containing DAI mutants deficient in nucleic acid binding are resistant to IAV-triggered necroptosis and apoptosis. DAI-deficient mice fail to control IAV replication and succumb to lethal respiratory infection. These results identify DAI as a link between IAV replication and RIPK3 activation and implicate DAI as a sensor of RNA viruses.
Publication
Journal: Trends in Microbiology
November/16/2014
Abstract
Programmed cell death is an important facet of host-pathogen interactions. Although apoptosis has long been implicated as the major form of programmed cell death in host defense, the past decade has seen the emergence of other forms of regulated death, including programmed necrosis. While the molecular mechanisms of programmed necrosis continue to be unveiled, an increasing number of viral and bacterial pathogens induce this form of death in host cells, with important consequences for infection, control, and pathogenesis. Moreover, pathogen strategies to manipulate or utilize this pathway are now being discovered. In this review, we focus on a variety of viral and bacterial pathogens where a role for programmed necrosis is starting to be appreciated. In particular, we focus on the mechanistic details of how the host or the pathogen might appropriate this pathway for its own benefit.
Publication
Journal: Cell Cycle
January/17/2011
Abstract
Caspase-independent programmed necrosis is a highly regulated cellular demise that displays morphological and biochemical necrotic hallmarks, such as an earlier permeability of the plasma membrane and lactate dehydrogenase (LDH) leakiness. This form of programmed cell death (PCD) is regulated by AIF, a FAD-dependent oxidoreductase, which is released from the mitochondria to the nucleus where it induces chromatin tcondensation and DNA fragmentation. Some years ago, it was established that the sequential activation of poly(ADP-ribose) polymerase- 1 (PARP-1), calpains and Bax regulates the mitochondrial AIF release associated to programmed necrosis. But, what happens when AIF is in the nucleus? How does this protein induce chromatinolysis and programmed necrosis? Recently, we have unraveled some of the mechanisms underlying the nuclear action of AIF in this type of caspase-independent cell death. Indeed, AIF plays a key role in programmed necrosis by its ability to organize a DNA-degrading complex with H2AX and Cyclophiline A (CypA). The AIF/H2AX link is indeed a critical event and explains the nuclear AIF apoptogenic action. In the present article, we outline the current knowledge on cell death by programmed necrosis and discuss the relevance of the AIF/H2AX/CypA DNA-degrading complex in the regulation of this original form of cell death.
Publication
Journal: Cell
May/8/2017
Abstract
Caspases were originally identified as important mediators of inflammatory response and apoptosis. Recent discoveries, however, have unveiled their roles in mediating and suppressing two regulated forms of necrotic cell death, termed pyroptosis and necroptosis, respectively. These recent advances have significantly expanded our understanding of the roles of caspases in regulating development, adult homeostasis, and host defense response.
Publication
Journal: Cell Reports
November/12/2017
Abstract
Recruitment of the deubiquitinase CYLD to signaling complexes is mediated by its interaction with HOIP, the catalytically active component of the linear ubiquitin chain assembly complex (LUBAC). Here, we identify SPATA2 as a constitutive direct binding partner of HOIP that bridges the interaction between CYLD and HOIP. SPATA2 recruitment to TNFR1- and NOD2-signaling complexes is dependent on HOIP, and loss of SPATA2 abolishes CYLD recruitment. Deficiency in SPATA2 exerts limited effects on gene activation pathways but diminishes necroptosis induced by tumor necrosis factor (TNF), resembling loss of CYLD. In summary, we describe SPATA2 as a previously unrecognized factor in LUBAC-dependent signaling pathways that serves as an adaptor between HOIP and CYLD, thereby enabling recruitment of CYLD to signaling complexes.
load more...