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RIPK3 activation leads to cytokine synthesis that continues after loss of cell membrane integrity

ABSTRACT: Necroptosis is a form of programmed cell death that is defined by activation of the kinase RIPK3, and subsequent cell membrane permeabilization by the effector MLKL. In addition to triggering cell death, RIPK3 activation can promote immune responses through the production of cytokines and chemokines. How active cytokine production is coordinated with the terminal process of necroptosis is unclear. Here, we report that cytokine production continues within necroptotic cells after cells have lost plasma membrane integrity and irreversibly commited to death. The continued production of inflammatory mediators was dependent on mRNA translation, and required maintanence of endoplasmic reticulum integrity, which remained in tact after plasma membrane integrity was lost. The continued translation of cytokines by cellular corpses contributed to necroptotic cell uptake by innate immune cells, as well as priming of adaptive immune responses to antigens associated with necroptotic corpses. These findings imply that necroptosis may represent a program in which cell death and production of inflammatory mediators are coordinated to optimize the immunogenicity of necroptotic cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE134234 | GEO | 2019/07/13

REPOSITORIES: GEO

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Components of the ESCRT machinery act downstream of MLKL to regulate necroptotic cell death and its consequences

Project description: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 (Ca++) 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. Components of the ESCRT machinery are required for formation of these bubbles, and act to sustain survival of the cell when MLKL activation is limited or reversed. Under conditions of necroptotic cell death, ESCRT controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT, cells undergoing necroptosis can express chemokines and other regulatory molecules, and promote antigenic cross-priming of CD8+ T cells.

2017-06-16 | GSE85660 | GEO

Spatiotemporal Control of InflammatoryLytic Cell Death Through Optogenetic Induction of RIPK3 Oligomerization

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Project description:Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators – Caspase-8, RIPK1, RIPK3 and MLKL – in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo.

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2023-06-06 | PXD042579 | Pride

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Oligomerisation-driven MLKL ubiquitylation antagonises necroptosis

Project description:Mixed lineage kinase domain-like (MLKL) is the executioner in the caspase 8-independent form of programmed cell death called necroptosis. Once Receptor Interacting serine/threonine Protein Kinase 3 (RIPK3) is activated by upstream cell death signals, it phosphorylates MLKL and triggers the oligomerization and membrane translocation required for MLKL induced membrane disruption. Besides phosphorylation, MLKL also undergoes ubiquitylation during the early stages of necroptosis, yet neither the mechanism nor the significance of this event has been demonstrated. Here we show that necroptosis-specific, multi-mono-ubiquitylation of MLKL occurs on biological membranes, and requires its activation and oligomerisation. Inactive MLKL mutants recruited to membranes during necroptosis are ubiquitylated but this results in their proteasome and lysosome dependent turnover. We identified several ubiquitylated lysines however mutation of these did not affect MLKL ubiquitylation in response to a necroptotic stimulus.

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Toxoplasma gondii secreted effectors co-opt host repressor complexes to inhibit necroptosis [II]

Project description:During infection, Toxoplasma gondii translocate effector proteins directly into the infected host cells to subvert various immune signaling pathways. We identified a novel secreted effector-TgNSM that localizes to the host cell nucleus. Mechanistically, TgNSM drives increased NCoR/SMRT repressor complex levels and enhances transcriptional repression of interferon regulated genes (ISGs). Type I and type II interferons can induce necroptosis by upregulating protein kinase PKR that induces the formation of a necrosome complex consisting of the RIPK1 and RIPK3. The necrosome then activates the pro-necroptotic protein MLKL to execute necrotic cell death. TgNSM acts together with another secreted effector TgIST, previously shown to down-modulate IFN-γ signaling. TgNSM and TgIST block IFN driven expression of PKR and MLKL, thus preventing host cell necroptotic death and assuring survival of intracellular cysts. The mechanism of action of TgNSM highlights a previously unappreciated role of NCoR/SMRT in regulation of necroptosis.

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Toxoplasma gondii secreted effectors co-opt host repressor complexes to inhibit necroptosis [I]

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Proteomic analysis of TRAIL-induced endogenous RIPK3-dependent necrosome complex

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