Ontology highlight
ABSTRACT:
PROVIDER: PRJNA802316 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17841905_1.fastq.gz | Fastqsanger.gz | |||
| SRR17841905_2.fastq.gz | Fastqsanger.gz | |||
| SRR17841906_1.fastq.gz | Fastqsanger.gz | |||
| SRR17841906_2.fastq.gz | Fastqsanger.gz |
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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.
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Project description:To revealed the significant involvement of GSDME-mediated pyroptosis in the pathogenesis and development of ICI-LI
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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.
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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。
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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.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) originates from normal pancreatic ducts where digestive juice is regularly produced. It remains unclear how PDAC can escape auto-digestion by digestive enzymes. Here we show that human PDAC tumor cells use gasdermin E (GSDME), a pore-forming protein upon caspase 3 cleavage, to mediate the digestive resistance. We find that GSDME facilitates the expression of mucins 1 and 13 in pancreatic tumor cells, which forms a barrier to prevent chymotrypsin-mediated destruction. Inoculation of GSDME-/- PDAC cells results in subcutaneous but not orthotopic tumor formation in mice. Either inhibiting or knocking out MUC1 or MUC13 abrogates orthotopic PDAC growth in NOD-SCID mice. Mechanistically, GSDME interacts with and transports transcription factor YBX1 into the nucleus where YBX1 directly promotes mucin expression. This GSDME-YBX1-mucin axis is also confirmed in PDAC patients. These findings uncover a unique survival mechanism of PDAC cells in pancreatic microenvironments, thus providing a potential target for PDAC treatment.
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Project description:A Cytotoxic T lymphocyte-inspired system capable of using ultralow-dose chemical drugs to manipulate cell death is needed to investigate the antitumour immunotherapy. Recent studies revealed pyroptosis, a proinflammatory type of cell death, could promote antitumour immune function. However, high-dose chemotherapy led to cytokine release syndrome by pyroptosis. Therefore, pyroptosis- inducing ultralow-dose chemotherapy was potential in preclinical and clinical research, but its efficacy, safety and the antitumour immune responses were not clear. Here, we established a near-infrared light controllable killing system (BIK system) by which ultralow-dose doxorubicin could be spatiotemporally transported to immunosuppressive tumour cells and mediate efficient pyroptosis. Compared with using DOX directly, the BIK system reduced total drug consumption to less than one- thirtieth the common dose in vitro. MPI imaging and fluorescence imaging showed our BIK system exhibited good tumour targeting and tumour penetration. We applied this system for pyroptosis-induced antitumor therapies, and the results showed that less than 43 µg kg-1 DOX was sufficient for GSDME-positive tumour regression with negligible injuries to major organs. Notably, the gasdermin-deficient 4T1 tumours could be controlled by combining BIK system with decitabine treatment. The antitumour immune function were proven to correlate with the impressive efficacy of pyroptosis-inducing ultralow-dose chemotherapy, and the concomitant immune memory prevented metastasis, but high-dose DOX led to poor T cells infiltration which caused immunosuppression and lung metastasis. Owing to the robust antitumour immune function induced by BIK system, advanced-stage bulky tumours could be controlled or shrunken by synergizing with anti-PD-1 therapy. This study provided new insights into the design of nanoassisted systems for activating the antitumour immune function by microstimulation; our application of the BIK system suggested that ultralow-dose chemotherapy was sufficient for inducing a robust pyroptosis-mediated antitumour immune function
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Project description:Summary Sodium 4-phenylbutyrate (Na-PBA), a histone deacetylase inhibitor, shows potential in mitigating acute lung injury (ALI) by addressing endothelial cell injury. In a lipopolysaccharide (LPS)-induced ALI mouse model, Na-PBA pretreatment reduced lung damage, pulmonary edema, and inflammatory markers, while decreasing oxidative stress and endothelial pyroptosis via the cytochrome c-caspase9-caspase3-GSDME pathway. In vitro studies with human umbilical vein endothelial cells (HUVECs) confirmed that Na-PBA enhanced PARK7 expression, which is crucial for its protective effects against oxidative damage and pyroptosis. The mechanism involves PARK7 stabilizing mitochondria and inhibiting cytochrome c leakage, leading to reduced caspase activation. Na-PBA's effects are mediated through upregulation of PARK7, potentially within a positive feedback loop involving NRF2. These findings identify a novel therapeutic strategy to alleviate endothelial injury in lung diseases.
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