Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis

Cai, Zhenyu; Jitkaew, Siriporn; Zhao, Jie; Chiang, Hsueh Cheng; Choksi, Swati; Liu, Jie; Ward, Yvona; Wu, Ling Gang; Liu, Zheng Gang

doi:10.1038/ncb2883

Cited by 1,102 publications

(978 citation statements)

References 33 publications

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“…Binding of the FHBD to negatively charged phosphatidylinositol phosphates has been proposed to recruit MLKL to the plasma membrane allowing it to directly permeabilize the membrane by forming a pore (Dondelinger et al , 2014; Su et al , 2014; Wang et al , 2014). Alternatively, it has been also proposed that plasma membrane‐bound MLKL recruits Ca 2+ or Na + ion channels to permeabilize the membrane (Cai et al , 2014; Chen et al , 2014). Thus, although the steps leading up to necroptosis are markedly different from pyroptosis, the execution of both types of lytic cell death involves the formation of plasma membrane pores.…”

Section: Discussionmentioning

confidence: 99%

GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death

et al. 2016

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Pyroptosis is a lytic type of cell death that is initiated by inflammatory caspases. These caspases are activated within multi‐protein inflammasome complexes that assemble in response to pathogens and endogenous danger signals. Pyroptotic cell death has been proposed to proceed via the formation of a plasma membrane pore, but the underlying molecular mechanism has remained unclear. Recently, gasdermin D (GSDMD), a member of the ill‐characterized gasdermin protein family, was identified as a caspase substrate and an essential mediator of pyroptosis. GSDMD is thus a candidate for pyroptotic pore formation. Here, we characterize GSDMD function in live cells and in vitro. We show that the N‐terminal fragment of caspase‐1‐cleaved GSDMD rapidly targets the membrane fraction of macrophages and that it induces the formation of a plasma membrane pore. In vitro, the N‐terminal fragment of caspase‐1‐cleaved recombinant GSDMD tightly binds liposomes and forms large permeability pores. Visualization of liposome‐inserted GSDMD at nanometer resolution by cryo‐electron and atomic force microscopy shows circular pores with variable ring diameters around 20 nm. Overall, these data demonstrate that GSDMD is the direct and final executor of pyroptotic cell death.

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Section: Discussionmentioning

confidence: 99%

GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death

et al. 2016

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“…RIPK3 phosphorylates mixed lineage kinase domain-like (MLKL), which induces oligomerization of MLKL resulting in plasma membrane rupture. [67][68][69] In human cells, it has been proposed that MLKL modulates phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (Drp1), in which Drp1 mediates mitochondrial fragmentation, which is necessary for metabolic inactivation and induction of necroptosis. 69,70 However, recent evidence suggests that PGAM5 and Drp1 may not be required for execution of necroptosis in murine cells.…”

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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“…Phosphorylation of MLKL promotes its oligomerization and translocation to the plasma membrane where it interacts with phospholipids and compromises membrane integrity ultimately resulting in cell rupture. [88][89][90][91] MLKL also promotes the generation of reactive oxygen species (ROS) and late phase activation of JNK. 92 The increased production of ROS, especially by the mitochondria, has been strongly linked with mediating TNFinduced necrosis.…”

Section: Rip1 and Rip3 As Drivers Of Necroptosismentioning

confidence: 99%