RIPK3 activation leads to cytokine synthesis that continues after loss of cell membrane integrity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA554367 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9677600.fastq.gz | Fastqsanger.gz | |||
| SRR9677610.fastq.gz | Fastqsanger.gz | |||
| SRR9677601.fastq.gz | Fastqsanger.gz | |||
| SRR9677611.fastq.gz | Fastqsanger.gz | |||
| SRR9677602.fastq.gz | Fastqsanger.gz |
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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
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. RIPK3 activation can also promote immune responses via 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 even after they have lost cell membrane integrity and irreversibly committed to death. This continued cytokine production is dependent on mRNA translation and requires maintenance of endoplasmic reticulum integrity that remains after plasma membrane integrity is lost. The continued translation of cytokines by cellular corpses contributes to necroptotic cell uptake by innate immune cells and priming of adaptive immune responses to antigens associated with necroptotic corpses. These findings imply that cell death and production of inflammatory mediators are coordinated to optimize the immunogenicity of necroptotic cells.
| S-EPMC6857709 | biostudies-literature
Project description:Necroptosis is a programmed lytic cell death involving active cytokine production and plasma membrane rupture through distinct signaling cascades. However, it remains challenging to delineate this inflammatory cell death pathway at specific signaling nodes with spatiotemporal accuracy. To address this challenge, we developed an optogenetic system, termed Light-activatable Receptor-Interacting Protein Kinase 3 or La-RIPK3, to enable ligand-free, optical induction of RIPK3 oligomerization. La-RIPK3 activation dissects RIPK3-centric lytic cell death through the induction of RIPK3-containing necrosome, which mediates cytokine production and plasma membrane rupture. Bulk RNA-Seq analysis reveals that RIPK3 oligomerization results in partially overlapped gene expression compared to pharmacological induction of necroptosis. However, La-RIPK3 activates a group of genes likely regulated by RIPK3 kinase-independent processes. Using patterned light stimulation delivered by a spatial light modulator, we demonstrate precise spatiotemporal control of necroptosis in La-RIPK3-transduced HT-29 cells. Optogenetic control of proinflammatory lytic cell death could lead to the development of innovative experimental strategies to finetune the immune landscape for disease intervention.
2024-06-05 | GSE268650 | GEO
Project description:Plasma Membrane Integrity Signaling
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Project description:RIPK4 but not the related kinases RIPK1, RIPK2, and RIPK3 caused similar transcriptional changes to Wnt3a. PA1 cells were transfected by 8ug RIPK1, RIPK2, RIPK3, or RIPK4 for 48h, RNA were extracted and sequenced.
2013-02-04 | E-GEOD-43362 | biostudies-arrayexpress
Project description:Pathogen recognition receptors and TNF superfamily members engage Receptor Interacting Serine/threonine Kinase-3 (RIPK3) to activate programmed cell death, including MLKL-mediated necroptosis and caspase-8-dependent apoptosis. However, the post-translational control of RIPK3 signalling is not fully understood. Using mass-spectrometry, we identified a novel ubiquitylation site on murine RIPK3 beyond the RIP homotypic interaction motif (RHIM) on K469. Complementation of RIPK3-deficient cells with a Ripk3K469R mutant demonstrated that the decoration of RIPK3 K469 by ubiquitin limits both RIPK3-mediated caspase-8 activation and apoptotic killing, in addition to RIPK3 autophosphorylation and MLKL-mediated necroptosis. Unexpectedly, the overall ubiquitylation of mutant RIPK3K469R was enhanced, which largely resulted from additional RIPK3 ubiquitylation on K359. Loss of RIPK3 K359 ubiquitylation reduced RIPK3K469R hyper-ubiquitylation and limited the ability of Ripk3K469R/K469R to trigger enhanced killing. Ripk3K469R/K469R mice challenged with Salmonella displayed increased bacterial loads in the spleen and liver, with reduced IFN serum levels. Therefore, RIPK3 K469 ubiquitylation can function to prevent RIPK3 ubiquitylation on alternate lysine residues, which otherwise promote RIPK3 oligomerization and consequent cell death signalling.
2022-08-12 | PXD026533 | Pride
Project description:We identified TRIM28 as a co-repressor that regulates transcriptional activity during necroptosis. RIPK3 activation induces TRIM28 phosphorylation at serine 473, inhibiting its chromatin binding activity, thereby contributing to the transactivation of NF-κB and other transcription factors, such as SOX9. This leads to elevated cytokine expression, which then potentiates immunoregulatory processes, such as DC maturation. The expression of RIPK3 has a significant positive association with the tumor-infiltrating immune cells populations in various tumor type, thereby activating anti-cancer responses.
2021-06-25 | GSE178847 | GEO
Project description:This purpose of this experiment was to investigate the transcriptional differences between C57BL6, RIPK3 knock-out mice infected with influenza strain A/CA/04/2009 (H1N1) virus. Overview of Experiment: Groups of 6-8 week-old C57BL6 and RIPK3 knock-out mice were infected with influenza A/CA/04/2009 virus. Infections were done at 10^5 PFU or time-matched mock infected. Time points were 2 and 4 d.p.i. There were 2-3 animals/dose/time point. Lung samples were collected for virus load and transcriptional analysis. Weight loss and animal survival were also monitored.
2014-04-02 | E-GEOD-51526 | biostudies-arrayexpress
Project description:Here, we characterize RIPK3-dependent transcriptional responses in cortical neurons following infection with neurotropic flaviviruses. Neurons were infected with either Zika virus (ZIKV) strain MR766 at an MOI of 0.1, West Nile virus (WNV) strain TX 2002-HC at an MOI of 0.001, or a saline mock solution. Neurons were derived from mice lacking RIPK3 expression (Ripk3-/-) or wildtype controls. These studies revealed a number of antiviral genes whose upregulation following viral infection is absent in neurons lacking RIPK3, a subset of which were validated using qRT-PCR.
2018-11-06 | GSE122121 | GEO
Project description:Astrocyte activation is a common feature of neurodegenerative diseases. However, the ways in which dying neurons influence the activity of astrocytes is poorly understood. RIPK3 signaling has recently been described as a key regulator of neuroinflammation, but whether this kinase mediates astrocytic responsiveness to neuronal death has not yet been studied. Here, we used the MPTP model of Parkinson’s disease to show that activation of astrocytic RIPK3 drives dopaminergic cell death and axon damage. Transcriptomic profiling revealed that astrocytic RIPK3 promoted gene expression associated with neuroinflammation and movement disorders, and this coincided with significant engagement of DAMP signaling. Using human cell culture systems, we show that factors released from dying neurons signal through RAGE to induce RIPK3-dependent astrocyte activation. These findings highlight a mechanism of neuron-glia crosstalk in which neuronal death perpetuates further neurodegeneration by engaging inflammatory astrocyte activation via RIPK3.
2024-04-05 | GSE237891 | GEO