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PANoptosis, a combination of inflammatory cell death mechanisms, induced by Ophiobolin A in breast cancer cell lines

ABSTRACT: An unmet challenge in managing breast cancer is treatment failure due to resistance to apoptosis-inducing chemotherapies. Thus, it is important to identify novel non-apoptotic therapeutic agents. Several non-apoptotic programmed cell death pathways utilize specific cellular signaling events to trigger lytic and pro-inflammatory cell death. PANoptosis, which encompasses pyroptosis, apoptosis and necroptosis, is of paramount importance in the regulation of cell death and immune responses. Our study illustrates that ophiobolin A (OpA) is an anti-cancer agent that triggers lytic cell death in breast cancer cells, including triple-negative breast cancer (TNBC), via a mechanism dependent on RIPK1. This study reveals that OpA induces typical pyroptosis-like characteristics, including cellular swelling, plasma membrane rupture, GSDMD cleavage and release of cytokines in breast cancer cells. The involvement of caspase 3, RIPK1, and GSDMD suggests that PANoptosis is activated upon OpA treatment in breast cancer. The induction of pro-inflammatory cell death suggests potential applications for OpA in cancer treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277026 | GEO | 2024/09/17

REPOSITORIES: GEO

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Pyroptosis by Caspase11/4-Gasdermin-D Pathway in Alcoholic Hepatitis

Project description:Alcoholic hepatitis (AH) continues to be a disease with high mortality and no efficacious medical treatment. Although severe AH is presented as acute on chronic liver failure, what underlies this transition from chronic alcoholic steatohepatitis (ASH) to AH, is largely unknown. To address this question, unbiased RNA-seq and proteomic analyses were performed on livers of the recently developed AH mouse model which exhibits the shift to AH from chronic ASH upon weekly alcohol binge, and these results are compared with gene expression profiling data from AH patients. This cross-analysis has identified Casp11 (CASP4 in man) as a commonly upregulated gene known to be involved in non-canonical inflammasome pathway. Immunoblotting confirms CASP11/4 activation in AH mice but not in chronic ASH. Gasdermin-D (GSDMD) which induces pyroptosis (lytic cell death caused by bacterial infection) downstream of CASP11/4 activation, is also activated in AH livers. CASP11 deficiency reduces GSDMD activation, bacterial load in the liver, and the severity of AH. Conversely, the deficiency of IL-18, the key anti-microbial cytokine, aggravates hepatic bacterial load, GSDMD activation, and AH. Further, hepatocyte-specific expression of constitutively active GSDMD worsens hepatocellular lytic death and PMN inflammation. These results implicate pyroptosis induced by CASP11/4-GSDMD pathway in the pathogenesis of AH.

2017-03-31 | GSE97234 | GEO

Shigella Ubiquitin ligase IpaH7.8 targets gasdermin D for degradation to prevent pyroptosis and enable infection

Project description:The pore-forming protein gasdermin D (GSDMD) executes lytic cell death called pyroptosis to eliminate the replicative niche of intracellular pathogens. Evolution favors pathogens that circumvent this host defense mechanism. Here, we show that the Shigella ubiquitin ligase IpaH7.8 functions as an inhibitor of GSDMD. Shigella is an enteroinvasive bacterium that causes hemorrhagic gastroenteritis in primates, but not rodents. IpaH7.8 contributes to species specificity by ubiquitinating human, but not mouse, GSDMD and targeting it for proteasomal degradation. Accordingly, infection of human epithelial cells with IpaH7.8-deficient Shigella flexneri results in increased GSDMD-dependent cell death compared with wild type. Consistent with pyroptosis contributing to murine disease resistance, eliminating GSDMD from NLRC4-deficient mice, which are already sensitized to oral infection with Shigella flexneri, leads to further enhanced bacterial replication and increased disease severity. This work highlights a species-specific pathogen arms race focused on maintenance of host cell viability.

2022-03-01 | MSV000088966 | MassIVE

A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis [II]

Project description:Gasdermin D (GSDMD) is the executioner of pyroptosis, which is important for host defense against pathogen infection. After activation, caspase-mediated cleavage of GSDMD liberates an N-terminal fragment (GSDMD-NT), which oligomerizes and forms pores in the plasma membrane, leading to cell death and subsequent release of proinflammatory cytokines. How this process is spatiotemporally controlled to promote pyroptosis in cells has been a fundamental, unaddressed question. Here, we identify GSDMD as a substrate for reversible S-palmitoylation on cysteine 192 (Cys192) in response to lipopolysaccharide (LPS) stimulation. We found that the palmitoyl acyltransferase DHHC7palmitoylates GSDMD to direct its cleavage by caspases in pyroptosis by promoting the interaction of GSDMD and caspases. We further show that after GSDMD cleavage, palmitoylation of GSDMD-NTpromotes its plasma membrane translocation and binding, and then acyl protein thioesterase 2 (APT2) depalmitoylates GSDMD-NT to unmask the Cys192 residue to promote oxidation-mediated oligomerization and pyroptosis. Perturbation of either palmitoylation or depalmitoylation suppresses pyroptosis, extends the survival of mice from LPS-induced lethal septic shock and sensitizes mice to bacterial infection. Thus. our findings reveal a model through which a palmitoylation-depalmitoylationrelay spatially and temporally controls GSDMD activation in pyroptosis.

2024-02-25 | GSE252911 | GEO

A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis [I]

2024-02-25 | GSE252893 | GEO

Differences in gene expression between WT and IRF2 KO cells

Project description:Gasdermin-D (GSDMD) is cleaved by caspase-1/4/11 in response to canonical and non-canonical inflammasome activation. Upon cleavage, GSDMD oligomerizes and forms membrane pores, resulting in IL-1Î² secretion, pyroptotic cell death and inflammatory pathologies including periodic fever syndromes and septic shock â a plague on modern medicine. The transcriptional machinery that drives the expression of GSDMD is unknown. Here we show that IRF2, a member of the interferon-regulatory factor (IRF) family, is essential for the transcriptional activation of GSDMD. A forward genetic screen with ethyl-N-nitrosourea (ENU)-mutagenized mice unequivocally linked IRF2 to inflammasome signaling. Indeed, GSDMD transcript levels were highly attenuated in Irf2â/â macrophages upon Irf2 deficiency in macrophages, endothelial cells, and multiple organs, corresponding to attenuated IL-1Î² secretion and inhibited pyroptosis. Mechanistically, IRF2 binds a previously uncharacterized site within the GSDMD promoter to directly drive GSDMD transcription for execution of pyroptosis in response to canonical and non-canonical inflammasome activation. Our data illuminate a prominent transcriptional mechanism for the expression of GSDMD, a key mediator of inflammatory pathologies.

2019-05-21 | GSE130195 | GEO

GSDMD-mediated metabolic crosstalk licenses a pro-regenerative niche for tissue repair

Project description:The establishment of an early pro-regenerative niche is crucial for tissue regeneration. Gasdermin D (GSDMD)-dependent pyroptosis accounts for the release of inflammatory cytokines upon various insults. However, little is known about its role in tissue regeneration followed by homeostatic maintenance. Here, we show that macrophage GSDMD deficiency delayed tissue recovery, with little impact on the local inflammatory milieu or the lytic pyroptosis process. Metabolite secretome profiling of hyperactivated macrophages unveiled the non-canonical metabolite-secreting function of GSDMD. And we further identified 11,12-epoxyeicosatrienoic acid (11,12-EET) as a bioactive pro-healing oxylipin, secreted from hyperactive macrophages in a GSDMD-dependent manner. Indeed, accumulation of 11,12-EET by direct supplementation or deletion of its hydrolytic enzyme Ephx2 accelerated muscle regeneration. We further demonstrated that the Ephx2 level accumulated within aged muscle, which led to a decreased intramuscular 11,12-EET level. And consecutive 11,12-EET treatment rejuvenated aged muscle. Mechanistically, 11,12-EET amplifies fibroblast growth factor/FGF receptor (FGF-FGFR) signaling by modulating FGF liquid-liquid phase separation, hence boosting the activation and proliferation of muscle stem cells (MuSCs). These data depict a GSDMD-guided metabolite crosstalk between macrophages and MuSCs that governs the repair process, which offers new therapeutic insights for the regeneration of injured or aged tissues.

2024-07-29 | GSE250049 | GEO

Gasdermin D deficiency promotes antitumor immunity by upregulating Type I ISG program in Antigen-presenting cells in response to PD-L1 antibody treatment

Project description:The tumor immune microenvironment is complex in composition, function and dynamic, influencing the evolution of tumor, prognosis and response to immunotherapy. Recent studies have significantly advanced our knowledge of the roles of Gasdermin protein-mediated tumoral pyroptosis activated by caspases and granzymes from cytotoxic lymphocytes in facilitating the killing of tumor cells. However, the pyroptosis of immune cells in tumor microenvironment and their affecting the reprogram of the tumor microenvironment remains poorly understood. In this study, we find that Gasdermin D (GSDMD), among Gasdermin family proteins, is significantly positively correlated with the immune checkpoint signature, and inversely linked to the overall survival of cancer patients by the analysis with TCGA clinical data. Using conditional knockout of GSDMD together with immunofluorescence co-labeling and single-cell RNA sequencing (scRNA-seq), we demonstrate that GSDMD mainly on antigen-presenting cells (APCs) such as macrophages and dendritic cells (DCs) in tumor microenvironment, restrains anti-tumor immunity under the treatment of PD-L1 antibody. Loss of GSDMD in APCs enhanced Type I interferon-stimulated gene (ISG) program of such cells, which promotes antigen presentation of macrophages and DCs, and facilitates the production of CD8+ effector and functional T cell. We further demonstrate that GSDMD deficiency increases anti-tumor immunity in a cyclic GMP–AMP synthase (cGAS)-dependent manner. Moreover, pharmacological inhibition of GSDMD-mediated pyroptosis significantly improves anti-tumor immunity in combination with PD-L1 antibody immunotherapy. Together, our findings reveal an important role for GSDMD-mediated pyroptosis of APCs such as macrophages and DCs in regulating CD8+ T cell function and underscore the potential of GSDMD blockade in promoting anti-tumor immunity, which may help the development of cancer immunotherapy.

2022-10-05 | GSE198550 | GEO

Regulation of pyroptosis in radiation induces mouse intestine cells

Project description:Pyroptosis is a recently discovered form of lytic cell death that is characterized by cell swelling and formation of pores and large bubbles on the plasma membrane. We find radiation could induce pyroptosis in human colorectal cancer HCT116 cells, and irradiation induces pyroptosis in mouse normal intestine MODEK cells only after 36 hours and over 8.0 Gy. In view of the significant pyroptosis effect of MODE-K cells, we selected 4Gy and 12Gy, 24h and 48h for experiments. After ONT full-length transcriptome sequencing, the cell pyroptosis model can screen out the differential genes related to cell pyroptosis, which is helpful to further explore the mechanism of pyroptosis of MODE-K cells.

2024-08-01 | GSE211709 | GEO

Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway

Project description:The process of pyroptosis is mediated by inflammasomes and a downstream effector known as gasdermin D (GSDMD). Upon cleavage by inflammasome-associated caspases, the N-terminal domain of GSDMD forms membrane pores that promote cytolysis. Numerous proteins promote GSDMD cleavage, but none are known to be required for pore formation after GSDMD cleavage. Herein, we report a forward genetic screen that identified the Ragulator-Rag complex as being necessary for GSDMD pore formation and pyroptosis in macrophages. Mechanistic analysis revealed that Ragulator-Rag is not required for GSDMD cleavage upon inflammasome activation, but rather promotes GSDMD oligomerization in the plasma membrane. Defects in GSDMD oligomerization and pore formation can be rescued by mitochondrial poisons that stimulate reactive oxygen species (ROS) production, and ROS modulation impacts the ability of inflammasome pathways to promote pore formation downstream of GSDMD cleavage. These findings reveal an unexpected link between key regulators of immunity (inflammasome-GSDMD) and metabolism (Ragulator-Rag).

2021-06-29 | GSE179089 | GEO

The Card19 locus regulates apoptosis and pyroptosis downstream of caspase activation and gasdermin D cleavage independently from IL-1 cytokine release

Project description:Cell death plays a critical role in inflammatory responses. During pyroptosis, inflammatory caspases cleave Gasdermin D (GSDMD) to release an N-terminal fragment that generates plasma membrane pores that mediate cell lysis and IL-1 release. However, certain stimuli and cell types release IL-1 cytokines through GSDMD pores in cells that remain viable, a process termed hyperactivation. How these distinct cell fate choices are regulated downstream of GSDMD pore formation is unknown. Here, we demonstrate that the Card19 locus promotes lysis downstream of caspase activation. Despite being largely protected from cell death, CARD19-deficient macrophages had no defect in caspase activation, IL-1 secretion, or GSDMD cleavage. CARD19, a mitochondrial protein, was not responsible for the observed phenotypes, nor was the recently identified pore forming protein NINJ1 which regulates terminal pore formation during multiple forms of cell death. Furthermore, previously identified cell death phenotypes attributed to Sterile alpha and heat Armadillo motif-containing protein (SARM) were revealed to be caused by a passenger mutation. Importantly, Card19-/ mice had increased susceptibility to Yersinia infection, including increased mortality, higher bacterial burdens and pronounced splenomegaly. These findings implicate the Card19 locus as a factor that couples caspase processing and GSDMD cleavage to cell death, providing insight into how the checkpoint between hyperactivation and cell death is regulated.

2021-03-21 | GSE168489 | GEO

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