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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE252911 | GEO | 2024/02/25

REPOSITORIES: GEO

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

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 | GSE252893 | 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

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

A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis

Project description:A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis

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The Central Role of Gasdermin D in Asthmatic Airway Inflammation and Remodeling

Project description:Emerging evidence demonstrates that pyroptosis has been implicated in the pathogenesis of asthma. GSDMD is the pyroptosis executioner. The mechanism of GSDMD in asthma remains unclear. The aim of this study was to elucidate the potential role of GSDMD in asthmatic airway inflammation and remodeling. First, we performed immunofluorescent staining and ELISA to detect the protein levels of N-GSDMD in the airway epithelium and IL-18, IL-1β in serum of both asthma patients and the healthy individuals. We demonstrated that N-GSDMD, IL-18, and IL-1β were significantly increased in mild asthma compared with that from the controls. Then, wild type and Gsdmd-knock out (Gsdmd-/-) mice were used to establish asthma model. We isolated primary macrophages and performed histopathological staining, ELISA, flow cytometry to define the roles of GSDMD in allergic airway inflammation and tissue remodeling in vivo. We observed that the production of N-GSDMD, IL-18, and IL-1β were enhanced in OVA-induced asthma mice model. The knockout of Gsdmd resulted in attenuated N-GSDMD, IL-18, and IL-1β production in both bronchoalveolar lavage fluid (BALF) and lung tissue in asthmatic mice. In addition, Gsdmd-deficiency mice exhibit a significantly reduction in airway inflammation and remodeling, which might be associated with reduced Th17 type inflammation response and M2 polarization. Third, we explored the underlying mechanism of GSDMD in asthma by bulk RNA-sequencing. We found GSDMD may improve asthmatic airway inflammation and remodeling through regulating macrophage adhesion and migration, and then lead to M2 polarization by targeting Notch signaling pathway. These findings demonstrated that GSDMD plays a critical role in the pathogenesis of allergic inflammation and tissue remodeling.

2024-05-31 | GSE249948 | 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

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

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

| PRJNA1063222 | ENA

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

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

| PRJNA1063180 | ENA

Non-lethal stress-induced discrete proteolysis is caspase-3/7 dependent

Project description:Cells are in constant adaptation to environmental changes to insure their proper functioning. When exposed to stresses, cells activate specific pathways to elicit adaptive modifications. Those changes can be mediated by selective modulation of gene and protein expression as well as by post-translational modifications, such as phosphorylation and proteolytic processing. Protein cleavage, as a controlled and limited post-translational modification, is involved in diverse physiological processes such as the maintenance of protein homeostasis, activation of repair pathways, apoptosis and the regulation of proliferation. Here we assessed by quantitative proteomics the proteolytic landscape in two cell lines subjected to low cisplatin concentrations used as a mild non-lethal stress paradigm. This landscape was compared to the one obtained in the same cells stimulated with cisplatin concentrations inducing apoptosis. These analyses were performed in wild-type cells and in cells lacking the two main executioner caspases: caspase-3 and caspase-7. Ninety proteins were found to be cleaved at one or a few sites (discrete cleavage) in low stress conditions compared to four hundred and forty in apoptotic cells. Many of the cleaved proteins in stressed cells were also found to be cleaved in apoptotic conditions. As expected in apoptotic cells, ~80% of the cleavage events were dependent on caspase 3/caspase 7. Strikingly, upon exposure to non-lethal stresses, no discrete cleavage was detected in cells lacking caspase-3 and caspase-7. This indicates that the proteolytic landscape in stressed viable cells fully depends on the activity of executioner caspases. These results suggest that the so-called executioner caspases fulfill important stress adaptive responses distinct from their role in apoptosis.

2021-07-07 | PXD023488 | Pride

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