LncRNA Malat1 suppresses pyroptosis and T cell-mediated killing of incipient metastatic cells [RNA-seq_4T1]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA761301 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15736858.fastq.gz | Fastqsanger.gz | |||
| SRR15736859.fastq.gz | Fastqsanger.gz | |||
| SRR15736860.fastq.gz | Fastqsanger.gz | |||
| SRR15736861.fastq.gz | Fastqsanger.gz | |||
| SRR15736862.fastq.gz | Fastqsanger.gz |
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Project description:Malat1 was KO using paired gRNA CRISPR-cas9 system from 4T1 cells.
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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:Previously, lncRNA Malat1 knockout mice were generated by insertional inactivation. By crossing this line to MMTV-PyMT mammary tumor mouse model, we produced PyMT;Malat1 wild-type (WT) and PyMT;Malat1 knockout (KO). Furthermore, we generated Malat1 transgenic mice by targeting ROSA26 locus and bred them to PyMT;Malat1 knockout mice to produce Malat1-rescued PyMT;Malat1 knockout;Malat1 transgenic animals (TG). Using mammary tumors from the three groups of animals, we performed RNA-Seq analysis to identify differentially up-regulated genes in KO tumors to find novel target genes of YAP-TEAD pathway.
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Project description:LncRNA Malat1 inhibition of TDP43 cleavage suppresses IRF3-initiated antiviral innate immunity
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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.
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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.
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Project description:Pancreatic cancer is one of the most deadly malignant tumors, and its treatment is scarce. This study found that arachidonic acid can induce pyroptosis of pancreatic cancer both in vitro and in vivo, and can cause immune cell infiltration. Arachidonic acid can be used as a tumor killing drug and an immunotherapy activator, which provides a new idea for the treatment of pancreatic cancer.
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Project description:Malat1 is an abundant long noncoding RNA that localizes to nuclear bodies known as nuclear speckles, which contain a distinct set of pre-mRNA processing factors. Previous in vitro studies have demonstrated that Malat1 interacts with pre-mRNA splicing factors, including the serine- and arginine-rich (SR) family of proteins, and regulates a variety of biological processes, including cancer cell migration, synapse formation, cell cycle progression, and responses to serum stimulation. To address the physiological function of Malat1 in a living organism, we generated Malat1-KO (KO) mice using homologous recombination. Unexpectedly, the Malat1-KO mice were viable and fertile, showing no apparent phenotypes. Nuclear speckle markers were also correctly localized in cells that lacked Malat1. However, the cellular levels of another long noncoding RNA, Neat1, which is an architectural component of nuclear bodies known as paraspeckles, were downregulated in a particular set of tissues and cells lacking Malat1. To address if the the absence of Malat1 affects the expression of other genes, including other long noncoding RNA, microarrays were used to study the impact of knocking-out Malat1 on global gene expression in mouse embryonic fibroblasts (MEFs). MEFs were prepared from E13.5 mouse embryos from wildtype and Malat1 knock-out mice. RNA harvested from these cells were hybridized to Affymetirx mouse gene expression array.
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Project description:Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA) that was first discovered as a prognostic marker for lung cancer metastasis. MALAT1 has been implicated in the tumorigenesis of numerous tumor types. To further delineate the underlying molecular mechanism, we established a high-throughput strategy to characterize the interacting proteins of MALAT1 by combining RNA pull down, quantitative proteomics, bioinformatics analysis, and experimental validation.
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Project description:Malat1 is an abundant long noncoding RNA that localizes to nuclear bodies known as nuclear speckles, which contain a distinct set of pre-mRNA processing factors. Previous in vitro studies have demonstrated that Malat1 interacts with pre-mRNA splicing factors, including the serine- and arginine-rich (SR) family of proteins, and regulates a variety of biological processes, including cancer cell migration, synapse formation, cell cycle progression, and responses to serum stimulation. To address the physiological function of Malat1 in a living organism, we generated Malat1-KO (KO) mice using homologous recombination. Unexpectedly, the Malat1-KO mice were viable and fertile, showing no apparent phenotypes. Nuclear speckle markers were also correctly localized in cells that lacked Malat1. However, the cellular levels of another long noncoding RNA, Neat1, which is an architectural component of nuclear bodies known as paraspeckles, were downregulated in a particular set of tissues and cells lacking Malat1. To address if the absence of Malat1 affects the expression of other genes, including other long noncoding RNA, microarrays were used to study the impact of knocking-out Malat1 on global gene expression in hippocampal neurons. Hippocampi were dissected from two sets of wildtype and Malat1 knock-out mice and RNA from these neurons were hybridized to Affymetix mouse exon array. Individual animals from each pairs of wildtype and knock-out are littermates.
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