Necroptosis Execution Is Mediated by Plasma Membrane Nanopores Independent of Calcium

Ros, Uris; Peña‐Blanco, Aida; Hänggi, Kay; Kunzendorf, Ulrich; Krautwald, Stefan; Wong, Wendy Wei-Lynn; García‐Sáez, Ana J.

doi:10.1016/j.celrep.2017.03.024

Cited by 108 publications

(120 citation statements)

References 55 publications

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“…According to another model, execution probably occurs indirectly by the MLKL‐dependent engagement of ion channels, which leads to influx of sodium or calcium ions . In necroptosis, the plasma membrane is permeabilized by osmotic forces and the formation of nanopores of about 4 nm in the plasma membrane, which represent a hallmark in necroptosis execution. Although studies on the role of MLKL and PIPs in permeabilization of the plasma membrane highlight the role of lipids in necroptosis, it is unknown whether lipids or disruption of lipid metabolic pathways modulate necroptosis …”

Section: Necroptosis: Molecular Mechanisms In Briefmentioning

confidence: 99%

Necroptotic cell death in anti‐cancer therapy

Krysko

Aaes

Kagan

et al. 2017

Immunological Reviews

131

103

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Necroptosis is one the best-characterized forms of regulated necrosis. Necroptosis is mediated by the kinase activities of receptor interacting protein kinase-1 and receptor interacting protein kinase-3, which eventually lead to the activation of mixed lineage kinase domain-like. Necroptosis is characterized by rapid permeabilization of the plasma membrane, which is associated with the release of the cell content and subsequent exposure of damage-associated molecular patterns (DAMPs) and cytokines/chemokines. This release underlies the immunogenic nature of necroptotic cancer cells and their ability to induce efficient anti-tumor immunity. Triggering necroptosis has become especially important in experimental cancer treatments as an alternative to triggering apoptosis because one of the hallmarks of cancer is the blockade or evasion of apoptosis. In this review, we discuss recent advances in necroptosis research and the functional consequences of necroptotic cancer cell death, with focus on its immunogenicity and its role in the activation of anti-tumor immunity. Next, we discuss the molecular mechanisms of phosphatidylserine exposure during necroptosis and its role in the recognition of necroptotic cells. We also highlight the complex role of the necroptotic pathway in tumor promotion and suppression and in metastasis. Future studies will show whether necroptosis is truly a better strategy to overcome apoptosis resistance and provide the insights needed for development of novel treatment strategies for cancer.

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Section: Necroptosis: Molecular Mechanisms In Briefmentioning

confidence: 99%

Necroptotic cell death in anti‐cancer therapy

Krysko

Aaes

Kagan

et al. 2017

Immunological Reviews

131

103

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“…Activated RIPK3 is then thought to recruit MLKL and phosphorylate its pseudokinase domain to induce MLKL's exposure of the N-terminal four-helix bundle (executioner) domain, MLKL oligomerisation, membrane translocation, and permeabilisation ( Figure 1). Whereas the mechanism of MLKL-mediated plasma membrane permeabilisation is still widely debated (Petrie et al, 2017;Ros et al, 2017), a key outcome is the release of DAMPs and other inflammatory signalling molecules, including cytokines (Li et al, 2012;Pasparakis et al, 2015). RHIM sequences from other cellular proteins (Lin et al, 2016;Newton et al, 2016a;Upton et al, 2012), and TRIF (He et al, 2011;Pasparakis et al, 2015), are thought to act as glue to facilitate RIPK3 higher order complex assembly, and depending on the context, the RHIM of RIPK1 may promote or negate RIPK3 activation (Newton et al, 2016b).…”

Section: What Is Necroptosis?mentioning

confidence: 99%

Down the rabbit hole: Is necroptosis truly an innate response to infection?

Pearson

Murphy

2017

Cellular Microbiology

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Pathogenic microbes have evolved countless sophisticated mechanisms to subvert host immune responses and cause disease. Understanding evasion strategies employed by pathogens has led to numerous discoveries on specific host cell processes that are critical for controlling infection. Programmed cell death (PCD) is a key host defence to microbial infection, as well as being critical for organ development and cellular homeostasis in multicellular organisms. Much of our current understanding of PCD as a host response to infection has stemmed from the discovery and study of viral inhibitors of apoptosis, and more recently viral inhibition of the newly characterised from of PCD termed necroptosis, the mechanisms of which are still under intense investigation. Many bacterial pathogens also encode inhibitors of PCD, yet these discoveries are relatively more recent and thus the biological significance of such mechanisms is still under debate. In this viewpoint article, we will argue the concept that necroptosis is merely a "back-up" mechanism in the event that apoptosis is inhibited, or whether it is a true host innate response to infection that has evolved in response to a growing arsenal of microbial evasion strategies.

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“…S7). Although not formally ruled out here, MLKL-dependent Ca 2+ flux was shown to occur rather lately in necroptotic HT-29 cells, concomitantly to the loss of PM integrity [28]. Intriguingly, we noted that PANX1 and MLKL were cleaved by non-caspase proteases in a PANX1-dependent manner during necroptosis.…”

Section: Discussionmentioning

confidence: 52%

Pannexin-1 Channels govern the Generation of Necroptotic small Extracellular Vesicles

Douanne

André-Grégoire

Feyeux

et al. 2019

Preprint

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The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) controls the execution of necroptosis, a regulated form of necrosis that occurs in apoptosis-deficient conditions. Active oligomerized MLKL triggers the exposure of phosphatidylserine residues on the cell surface and disrupts the plasma membrane integrity by forming lytic pores. MLKL also governs the biogenesis and shedding of proinflammatory small extracellular vesicles (EVs) during the early steps of necroptosis, however the molecular basis is unknown. Here, we find that MLKL oligomers activate plasma membrane Pannexin-1 (PANX1) channels, concomitantly to the loss of phosphatidylserine asymmetry. This plasma membrane "leakiness" requires the Rab GTPase Rab27 isoforms, which usher the small EVs to their release. Conversely, PANX1 knockdown disorganized the small EVs machinery and precludes vesicles extrusion. These data identify a novel signaling nexus between MLKL, Rab27, and PANX1, and propose ways to interfere with small EV generation.allows the pseudokinase to insert into the PM and compromise cell-membrane integrity leading to the cell's demise [10][11][12][13][14].Shortly before PM collapses, MLKL oligomers trigger the exposure of phosphatidylserine (PS) residues at the cell surface, acting as "eat-me" signals for the surrounding immune cells [15,16]. However, cells with phosphorylated MLKL and flipped PS are not necessarily committed to death and can "resuscitate" provided the stimulus is removed in a timely manner [16,17]. MLKL also governs the dynamic biogenesis and release of small extracellular vesicles (EVs) during the early stages of necroptosis by cells which are otherwise viable [15,18]. These membrane vesicles containing cytosolic material emerge as potent vectors of intercellular communication [19]. How MLKL controls these many functions continues to be elucidated. Hints may come from the discovery that active MLKL targets intracellular organelles in addition to the PM [3], and was demonstrated to regulate constitutive endosomal trafficking [18]. Furthermore, MLKL silencing causes a drastic reduction in the number of nascent intracellular small EVs, also called intraluminal vesicles (ILVs), which are no longer expelled into the extracellular space [18].The mechanism by which MLKL licenses the biogenesis and the release of small EVs out of the cells remains poorly understood. Here, we find that MLKL oligomers also promote the activation of PANX1 hemichannels via the Rab27 small GTPase subfamily during the early stages of necroptosis. Although this Rab27-PANX1 axis appears dispensable for the proper execution of the necroptotic program, it tightly regulates the generation of small EVs. RESULTS MLKL promotes "Leakiness" of the Plasma Membrane during NecroptosisHT-29 colon cancer cells, which constitute a classical model for necroptosis [4,5] were treated with TNFa (T) in the presence of the pan-caspase inhibitor Q-VD-OPh (Q), together with the Smac mimetic Birinapant (S) [20]. Necroptosis was then v...

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Necroptosis Execution Is Mediated by Plasma Membrane Nanopores Independent of Calcium

Cited by 108 publications

References 55 publications

Necroptotic cell death in anti‐cancer therapy

Necroptotic cell death in anti‐cancer therapy

Down the rabbit hole: Is necroptosis truly an innate response to infection?

Pannexin-1 Channels govern the Generation of Necroptotic small Extracellular Vesicles

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