Depletion of RIPK3 or MLKL blocks TNF-driven necroptosis and switches towards a delayed RIPK1 kinase-dependent apoptosis

Remijsen, Quinten; Goossens, Vera; Grootjans, Sasker; Haute, Chris Van den; Vanlangenakker, Nele; Dondelinger, Yves; Roelandt, Ria; Bruggeman, Inge; Gonçalves, Amanda; Bertrand, Mathieu J.M.; Baekelandt, Veerle; Takahashi, Nozomi; Berghe, Tom Vanden; Vandenabeele, Peter

doi:10.1038/cddis.2013.531

Cited by 170 publications

(157 citation statements)

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“…13,14 The relevance of the former is unclear because cardiolipin is believed to be exclusively mitochondrially localized, yet mitochondria and the PGAM5-Drp1 mitochondrial fragmentation pathway are not universally required for necroptosis. 5,20,[26][27][28] Here, we observed that the 4HB domains of mouse and frog MLKL, which kill MDFs, and human and chicken 4HB domains, which do not, could permeabilize membranes and exhibited a clear preference for plasma membrane over mitochondrial composition liposomes. Unexpectedly, full-length human, frog and chicken MLKL were more potent and rapid inducers of membrane permeabilization than the recombinant NTDs alone, suggesting a function for the pseudokinase domain in augmenting 4HB domain-mediated membrane permeabilization.…”

Section: Discussionmentioning

confidence: 80%

Evolutionary divergence of the necroptosis effector MLKL

et al. 2016

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The pseudokinase, MLKL (mixed-lineage kinase domain-like), is the most terminal obligatory component of the necroptosis cell death pathway known. Phosphorylation of the MLKL pseudokinase domain by the protein kinase, receptor interacting protein kinase-3 (RIPK3), is known to be the key step in MLKL activation. This phosphorylation event is believed to trigger a molecular switch, leading to exposure of the N-terminal four-helix bundle (4HB) domain of MLKL, its oligomerization, membrane translocation and ultimately cell death. To examine how well this process is evolutionarily conserved, we analysed the function of MLKL orthologues. Surprisingly, and unlike their mouse, horse and frog counterparts, human, chicken and stickleback 4HB domains were unable to induce cell death when expressed in murine fibroblasts. Forced dimerization of the human MLKL 4HB domain overcame this defect and triggered cell death in human and mouse cell lines. Furthermore, recombinant proteins from mouse, frog, human and chicken MLKL, all of which contained a 4HB domain, permeabilized liposomes, and were most effective on those designed to mimic plasma membrane composition. These studies demonstrate that the membrane-permeabilization function of the 4HB domain is evolutionarily conserved, but reveal that execution of necroptotic death by it relies on additional factors that are poorly conserved even among closely related species. Necroptosis is a form of programmed cell death that can be induced following ligation of death ligand and Toll-like receptors (TLRs). Most experimental work has focused on necroptosis induced by tumour necrosis factor (TNF). The key effectors in the pathway are the protein kinases, receptor interacting protein kinase (RIPK)-1 and RIPK3, 1-4 and the mixed-lineage kinase domain-like (MLKL) pseudokinase. [5][6][7][8] RIPK3 phosphorylates the pseudokinase domain of MLKL, the most terminal known essential component of the pathway, 5,6 which is believed to induce a conformational change and unleash the N-terminal four-helix bundle (4HB) domain of MLKL: an executioner domain. 5,9,10 Several models have been proposed for how this 4HB domain might induce cell death, including activation of downstream effectors, such as ion channels, 11,12 direct permeabilization of membranes and/or formation of a transmembrane pore, 13,14 all of which remain the subject of debate. The consensus from these and other studies is that in order to kill, MLKL must translocate to membranes and assemble into high molecular weight signalling complexes, which are likely to be MLKL oligomers, although the stoichiometry of these MLKL oligomers remains an open question. [10][11][12][13][14] Nonetheless, phosphorylation appears to be a key cue for MLKL activation 15 and, as the most terminal known post-translational modification in the pathway, could potentially be utilized as a biomarker in pathologies arising from necroptotic cell death. 14,16 A model whereby RIPK3-mediated phosphorylation of the MLKL pseudokinase domain activation loop (S345 in mouse;...

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Section: Discussionmentioning

confidence: 80%

Evolutionary divergence of the necroptosis effector MLKL

et al. 2016

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“…69,70 However, recent evidence suggests that PGAM5 and Drp1 may not be required for execution of necroptosis in murine cells. 71,72 Nonetheless, catalytically active RIPK1 and RIPK3 are important for stable RIPK1-RIPK3 complex formation and subsequent execution of necroptotic cell death. [73][74][75] In this context, necrostatin-1 is widely used for improving tissue damage mediated by necroptosis induction.…”

Section: Tak1 As a Necroptosis Inducermentioning

confidence: 99%

TAK1 control of cell death

2014

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Programmed cell death, a physiologic process for removing cells, is critically important in normal development and for elimination of damaged cells. Conversely, unattended cell death contributes to a variety of human disease pathogenesis. Thus, precise understanding of molecular mechanisms underlying control of cell death is important and relevant to public health. Recent studies emphasize that transforming growth factor-b-activated kinase 1 (TAK1) is a central regulator of cell death and is activated through a diverse set of intra-and extracellular stimuli. The physiologic importance of TAK1 and TAK1-binding proteins in cell survival and death has been demonstrated using a number of genetically engineered mice. These studies uncover an indispensable role of TAK1 and its binding proteins for maintenance of cell viability and tissue homeostasis in a variety of organs. TAK1 is known to control cell viability and inflammation through activating downstream effectors such as NF-jB and mitogen-activated protein kinases (MAPKs). It is also emerging that TAK1 regulates cell survival not solely through NF-jB but also through NF-jB-independent pathways such as oxidative stress and receptor-interacting protein kinase 1 (RIPK1) kinase activity-dependent pathway. Moreover, recent studies have identified TAK1's seemingly paradoxical role to induce programmed necrosis, also referred to as necroptosis. This review summarizes the consequences of TAK1 deficiency in different cell and tissue types from the perspective of cell death and also focuses on the mechanism by which TAK1 complex inhibits or promotes programmed cell death. This review serves to synthesize our current understanding of TAK1 in cell survival and death to identify promising directions for future research and TAK1's potential relevance to human disease pathogenesis.

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“…Such discrepancies may reflect varying effector mechanisms in different cells and species. 98 RIP kinases and innate immunity F Humphries et al…”

Section: Rip1 and Rip3 As Drivers Of Necroptosismentioning

confidence: 99%