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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166936 | GEO | 2021/05/27

REPOSITORIES: GEO

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

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.

2021-05-27 | GSE157018 | GEO

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

Project description: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.

2019-07-13 | GSE134234 | GEO

An immunohistochemical atlas of necroptotic pathway expression

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.

2024-04-17 | GSE262762 | GEO

RIPK3 is released into Extracellular Vesicles during Necroptosis through a Rab27 independent mechanism

Project description:Extracellular vesicles (EVs) are important mechanisms used by cells to release biomolecules. A common necroptosis effector— mixed lineage kinase like (MLKL)--- was recently found to participate in the biogenesis of small and large EVs independent of its function in necroptosis. The objective of the current study is to gain mechanistic insights into EV biogenesis during necroptosis. We performed mass spectrometry-based proteomics on EVs released by healthy or necroptotic cells. Necroptosis increased the number of EVs released and altered the protein contents within the EVs. Comparing to EVs released by healthy cells, EVs released during necroptosis contained markedly higher number of unique proteins. Receptor interacting protein kinase 3 (RIPK3) and MLKL were among the proteins enriched in EVs released during necroptosis. Further, MEFs derived from mice deficient of Rab27a and Rab27b showed diminished basal EV release but responded to necroptosis with enhanced EV biogenesis as the wildtype MEFs. In contrast, necroptosis-associated EVs was sensitive to Ca2+ depletion or lysosomal disruption. Neither treatments affected the RIPK3-mediated MLKL phosphorylation. Our data suggests that necroptosis switches EV biogenesis from a Rab27a/b dependent mechanism to a lysosomal mediated mechanism.

2022-08-14 | PXD031224 | Pride

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.

2021-04-28 | PXD015537 | Pride

Human cytomegalovirus protein pUL36: a dual cell death pathway inhibitor

Project description:Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of intrinsic, innate and adaptive viral immune evasion. Here, we employ multiplexed tandem mass tag-based proteomics to characterise host proteins targeted for degradation late during HCMV infection. This approach revealed that mixed lineage kinase domain-like protein (MLKL), a key terminal mediator of cellular necroptosis, was rapidly and persistently degraded by the minimally passaged HCMV strain Merlin but not the extensively passaged strain AD169. The strain Merlin viral inhibitor of apoptosis pUL36 was necessary and sufficient both to degrade MLKL and to inhibit necroptosis. Furthermore, mutation of pUL36 Cys131 abrogated MLKL degradation and restored necroptosis. As the same residue is also required for pUL36-mediated inhibition of apoptosis by preventing proteolytic activation of pro-caspase 8, we define pUL36 as a multifunctional inhibitor of both apoptotic and necroptotic cell death.

2020-07-10 | PXD017279 | Pride

PIP2 promotes MLKL-derived pathogenic process through enhancing its channel activity

Project description:PIP2 enhances MLKL channel activity in a direct interaction manner and this gain of function promotes both necroptosis and inflammation. Previous studies have reported that phospholipids assisted MLKL recruitment and translocation which facilitates its mediated function like liposome leaking. Here, our result support MLKL act as ion channel and is finely tuned by PIP2. In the immune process especially, PIP2, as an important modulator, promotes intracellular potassium depletion and trigger inflammation which mediated bythrough MLKL channel function. Defining the role of MLKL channel function in MLKL-induced necroptosis or other potential necroptotic models will extend our understanding of the programmed cell death and critically inform the development and testing of new disease-specific, Anti-inflammatory, therapeutic strategies.

2022-11-05 | PXD030814 | Pride

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

A necroptosis-independent function of RIPK3 promotes immune dysfunction and prevents control of chronic LCMV infection

Project description:Necroptosis is a lytic and inflammatory form of cell death that is highly constrained to mitigate detrimental collateral tissue damage and impaired immunity. These constraints make it difficult to define the relevance of necroptosis in diseases such as chronic and persistent viral infections and within individual organ systems. The role of necroptotic signalling is further complicated because proteins essential to this pathway, such as receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), have been implicated in roles outside of necroptotic signalling. We sought to address this issue by individually defining the role of RIPK3 and MLKL in chronic lymphocytic choriomeningitis virus (LCMV) infection. We investigated if necroptosis contributes to the death of LCMV-specific CD8+ T cells or virally infected target cells during infection. We provide evidence showing that necroptosis was redundant in the pathogenesis of acute forms of LCMV (Armstrong strain) and the early stages of chronic (Docile strain) LCMV infection in vivo. The number of immune cells, their specificity and reactivity towards viral antigens and viral loads are not altered in the absence of either MLKL or RIPK3 during acute and during the early stages of chronic LCMV infection. However, we identified that RIPK3 promotes immune dysfunction and prevents control of infection at later stages of chronic LCMV disease. This was not phenocopied by the loss of MLKL indicating that the phenotype was driven by a necroptosis-independent function of RIPK3. We provide evidence that RIPK3 signaling evoked a dysregulated type 1 interferone response which we linked to an impaired antiviral immune response and abrogated clearance of chronic LCMV infection.

2023-03-12 | GSE224066 | GEO

Proteomic analysis of necroptotic extracellular vesicles

Project description:Necroptosis is a regulated but inflammatory form of cell death. We and others have previously reported that necroptotic cells release extracellular vesicles (EVs). We found that necroptotic EVs are loaded with proteins, including the key necroptosis executor factor, phosphorylated mixed lineage kinase domain-like (pMLKL). However, the exact necroptotic EVs proteins composition and impact have not been delineated yet. To characterize their content, EVs from necroptotic and untreated U937 cells were isolated by ultracentrifugation and analyzed by mass spectrometry. A total of 3337 proteins were identified, sharing high similarity with exosome proteome databases. Unsupervised hierarchical clustering of identified proteins distinguished between necroptotic and control EVs. A total of 353 proteins was significantly upregulated in the necroptotic EVs. Among these are MLKL and caspase-8, as validated by immunoblot. Components of ESCRTIII machinery and inflammatory signaling were found to be enriched in the necroptotic EVs, as well as yet unreported components of vesicles formation and transport and necroptosis signaling pathways. Moreover, we show that necroptotic EVs can be phagocytosed by macrophages to modulate cytokine and chemokine secretion. Finally, we reveal that necroptotic EVs contain tumor neoantigen and are enriched with proteins annotated as “antigen processing and presentation” biological process. In summary, our study reveals a new layer of regulation during the early stage of necroptosis by the secretion of specific EVs that influence their microenvironment and may instigate innate and adaptive immune responses. Future investigation will shed light on new players in the necroptosis signaling and its related EVs, and will uncover the functional tasks accomplished by the cargo of these necroptotic EVs.

2021-11-11 | PXD018258 | Pride

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