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ABSTRACT: Inhibition of CDC20 potentiates anti-tumor immunity through facilitates GSDME-mediated pyroptosis in prostate cancer

PROVIDER: PRJNA882665 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21656200_1.fastq.gz	Fastqsanger.gz
	SRR21656200_2.fastq.gz	Fastqsanger.gz
	SRR21656201_1.fastq.gz	Fastqsanger.gz
	SRR21656201_2.fastq.gz	Fastqsanger.gz
	SRR21656196_1.fastq.gz	Fastqsanger.gz

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Revealing disulfide bond formation in GSDME upon UVC irradiation under non-reducing conditions

Project description:It is widely acknowledged that gasdermin family proteins, which are known as the executors of pyroptosis, undergo protease-mediated cleavage prior to inducing pyroptosis. Here, we unexpectedly discovered a non-canonical form of pyroptosis mediated by full-length GSDME (FL-GSDME) without any proteolytic cleavage. Upon intense ultraviolet (UV) irradiation-triggered DNA damage, hyperactivation of nuclear PARP1 led to extensive formation of poly(ADP-ribose) (PAR) polymers and then release to the cytoplasm.These PAR polymers activate PARP5 to catalyze GSDME PARylation, resulted in a conformational change in GSDME that relieved autoinhibition imposed by its C terminus on the N terminus. On the other hand, intense UV irradiation boosted mitochondrial fission-dependent generation of mitochondrial reactive oxygen species (mito-ROS), further promoting cytochrome c-catalyzed peroxidation of cardiolipin. This lipid-ROS signal was then sensed by PARylated-GSDME and then induced oxidative oligomerization of GSDME, which facilitated FL-GSDME plasma membrane targeting for perforation, eventually inducing pyroptosis. Reagents that concurrently stimulate PARPs activity and lipid-ROS also induced sequential modifications i.e., PARylation and oxidation of FL-GSDME and synergistically promoted pyroptotic cell death. Overall, our findings elucidate a novel mechanism underlying cleavage-independent function of GSDME in executing cell demise, further enriching the paradigms and cognition of FL-GSDME-mediated non-canonical pyroptosis.

2024-06-17 | PXD051840 | Pride

Project description:GSDME-mediated Pyroptosis Promotes Atherosclerosis

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Project description:GSDME-mediated Pyroptosis Promotes Atherosclerosis

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Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis

Project description:To revealed the significant involvement of GSDME-mediated pyroptosis in the pathogenesis and development of ICI-LI

2024-12-23 | GSE280068 | GEO

The collaboration of GSDMD and GSDME in folic acid (FA)-induced renal injury

Project description:Acute kidney injury(AKI) is associated with an increased risk of chronic kidney disease(CKD). There is still a lack of effective prevention for AKI-CKD transition. In the present study, we simultaneously explored the contribution of GSDMD and GSDME in folic acid (FA)-induced nephropathy, a model mimicking the essential components of the AKI-CKD transition. We found that blockage of both GSDMD and GSDME-mediated pyroptosis could have accumulative protection against FA-induced AKI-CKD transition. GSDME-mediated pyroptosis played a crucial role in tubular cell damage. GSDMD could exert important functions in infiltration of inflammatory cells and NETs formation. Pyroptotic tubular cells triggered NETs generation and macrophage polarization. NETs promoted macrophage-to-myofibroblast transition. Our results illustrated the orchestration of GSDMD and GSDME in AKI-CKD transition, providing new insights into the molecular mechanism for the clinical dilemma.

2024-10-31 | GSE245446 | 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.

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Immunomodulatory-Photodynamic Nanostimulators for Invoking Pyroptosis to Augment Tumor Immunotherapy

Project description:Acidic tumor microenvironment (TME)-evoked MRC nanoparticles (MRC NPs) co-delivering immune agonist RGX-104 and photosensitizer chlorine e6 (Ce6) are reported for pyroptosis-mediated immunotherapy. RGX-104 remodels TME by transcriptional activation of ApoE to regress myeloid-derived suppressor cells’ (MDSCs) activity, which neatly creates foreshadowing for intensifying pyroptosis. Considering Ce6-triggered photodynamic therapy (PDT) can strengthen oxidative stress and organelles destruction to increase immunogenicity, immunomodulatory-photodynamic MRC nanodrugs will implement an aforementioned two-pronged strategy to enhance gasdermin E (GSDME)-dependent pyroptosis. RNA-seq analysis of MRC at the cellular level is introduced to first elucidate the intimate relationship between RGX-104 acting on LXR/ApoE axis and pyroptosis, where RGX-104 provides the prerequisite for pyroptosis participating in antitumor therapy. Briefly, MRC with favorable biocompatibility tackles the obstacle of hydrophobic drugs delivery, and becomes a powerful pyroptosis inducer to reinforce immune efficacy. MRC-elicited pyroptosis in combination with anti-PD-1 blockade therapy boosts immune response in solid tumors, successfully arresting invasive metastasis and extending survival based on remarkable antitumor immunity. MRC may initiate a new window for immuno-photo pyroptosis stimulators augmenting pyroptosis-based immunotherapy. Owing to the transcriptome sequencing on 4T1 cells exposed to various treatment, pyroptosis mechanism of MRC was thoroughly analyzed via comparing the expression discrepancy among PBS, MRC, and MRC+L groups.

2023-08-13 | GSE240328 | GEO

The analysis of GSDME-NT binding proteins in the presence or absence of methionine

Project description:Our study identify that methionine inhibits N-terminus of GSDME (GSDME-NT) -mediated pyroptosis by dampening its endocytotic degradation. Thus，the binding proteins of GSDME-NT are detected in the presence or absence of Methionine for futher exploration。

2025-01-19 | PXD059954 |

Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis

Project description:Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis

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