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Excessive R-loop-induced mitochondrial-dependent epithelial cell necroptosis drives spontaneous intestinal inflammation

ABSTRACT: Excessive R-loop-induced mitochondrial-dependent epithelial cell necroptosis drives spontaneous intestinal inflammation

PROVIDER: PRJNA945464 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23879576_1.fastq.gz	Fastqsanger.gz
	SRR23879576_2.fastq.gz	Fastqsanger.gz
	SRR23879577_1.fastq.gz	Fastqsanger.gz
	SRR23879577_2.fastq.gz	Fastqsanger.gz
	SRR23879578_1.fastq.gz	Fastqsanger.gz

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Excessive R-loop-induced mitochondrial-dependent epithelial cell necroptosis drives spontaneous intestinal inflammation

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Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis

Project description:Caspase-8 and FADD play key roles in the regulation of cell death by necroptosis. The absence of either protein results in early embryonic lethality due to the activation of the kinase RIPK3 and its phosphorylation of the necroptosis executioner, MLKL. We genetically engineered and characterized a mouse model to monitor MLKL phosphorylation in the absence of necroptosis in vivo. Ablation of caspase-8 or FADD resulted in the transcriptional upregulation in several tissues of ZBP1, a cytosolic nucleic acid sensor capable of activating RIPK3, and ZBP1 was required for spontaneous phosphorylation of MLKL. Our findings provide a novel mechanism by which the FADD-Caspase-8 complex prevents necroptosis.

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SETDB1 safeguards genome stability against necroptosis and bowel inflammation (ChIP-seq)

Project description:The aetiology of bowel inflammatory disease (IBD) is a multifactorial interplay between heredity and environment1-3. Here we report SETDB1, a histone methyltransferase (HMTs) for histone H3 lysine 9 trimethylation (H3K9me3) whose deficiency participates in the pathogenesis of IBD. We found that SETDB1 level decreased in IBD patients and that mice with reduced SETDB1 in intestinal stem cells (ISCs) developed spontaneous terminal ileitis and colitis. SETDB1 safeguards genome stability4, of which the loss in ISCs released repression of endogenous retrovirus (ERVs), the retrovirus-like elements with long repeats that comprise ~8% of genome5. Excessive viral mimicry generated by motivated ERVs triggered Z-DNA-binding protein 1 (ZBP1) dependent necroptosis, which irreversibly disrupted the homeostasis of epithelial barrier and promoted bowel inflammation. Of note, genome instability, reactive ERVs, upregulation of ZBP1 and necroptosis were seen in IBD patients. Pharmaceutic inhibition of RIP3 showed curative effect in SETDB1 deficient mice, suggesting therapy targeting ISC necroptosis may represent a new approach for severe IBD treatment.

2020-01-01 | GSE129173 | GEO

Setdb1 safeguards genome stability against stem cell necroptosis and bowel inflammation (RNA-seq)

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Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis

Project description:Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis

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Sublethal necroptosis signaling promotes inflammation and liver cancer

Project description:We developed a genetic mouse model of chronic necroptosis activation in hepatocytes (in the presence of basal NF-kB activity) that lead to hepatocellular carcinoma. Blocking Necroptosis (RIP3) or NF-kB-(IKKβ) activation in those mice blocked hepatocarcinogenesis.

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The Role of Necroptosis-mediated Inflammation in Hepatocellular Carcinoma

Project description:Non-alcoholic hepatosteatosis (NASH) due to metabolic syndrome or diabetes mellitus has been identified as the fastest growing cause of hepatocellular carcinoma (HCC), the fourth leading cause of cancer related deaths in the world. Therapeutic options for HCC are limited, and survival after diagnosis is poor (>10%). Thus, a better understanding of the mechanisms that drive the progression of NASH to HCC is critical in developing new strategies to prevent/treat HCC. Chronic inflammation is a key player in the pathogenesis of HCC, however, pathways that drive chronic hepatic inflammation in NASH-driven HCC is not known. Necroptosis is a regulated mode of cell death that causes inflammation and is activated in the livers of patients with NASH. Therefore, we tested whether necroptosis-mediated inflammation plays a role in the progression of NASH to HCC in a mouse model of NASH-induced HCC.

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Quantitative analysis of phosphoproteome in necroptosis reveals a role of TRIM28 phosphorylation in promoting necroptosis-induced cytokine production

Project description:Necroptosis is a form of regulated necrotic cell death which promotes inflammation. In cells undergoing necroptosis, the activated RIPK1 kinase mediates the formation of RIPK1/RIPK3/MLKL complex to promote MLKL oligomerization and execution of necroptosis. RIPK1 kinase activity also promotes cell-autonomous activation of proinflammatory cytokine production in necroptosis. However, the signaling pathways downstream of RIPK1 kinase in necroptosis and how RIPK1 kinase activation controls inflammatory response induced by necroptosis are still largely unknown. Here we quantitatively measured the temporal dynamics of over 7000 confident phosphosites during necroptosis using mass spectrometry. Our study defined a RIPK1-dependent phosphorylation pattern in late necroptosis that is associated with a proinflammatory component marked by p-S473 TRIM28. We show that the activation of p38 MAPK mediated by oligomerized MLKL promotes the phosphorylation of S473 TRIM28, which in turn mediates inflammation during late necroptosis. Taken together, our study illustrates a mechanism by which p38 MAPK may be activated by oligomerized MLKL to promote inflammation in necroptosis.

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O-GlcNAcylation of RIPK1 Rescues Red Blood Cells from Necroptosis

Project description:Necroptosis is a type of cell death with excessive inflammation and organ damage in various human diseases. Although abnormal necroptosis is common in patients with neurodegenerative, cardiovascular, and infectious diseases, the mechanisms by which O-GlcNAcylation contributes to the regulation of necroptotic cell death are poorly understood. In this study, we reveal that O- GlcNAcylation of RIPK1 (receptor-interacting protein kinase1) was decreased in erythrocytes of the mouse injected with lipopolysaccharide, resulting in the acceleration of erythrocyte necroptosis through increased formation of RIPK1-RIPK3 complex. Mechanistically, we discovered that O- GlcNAcylation of RIPK1 at serine 331 in human (corresponding to serine 332 in mouse) inhibits 32 This is a provisional file, not the final typeset article phosphorylation of RIPK1 at serine 166, which is necessary for the necroptotic activity of RIPK1 and suppresses the formation of the RIPK1-RIPK3 complex in Ripk1 -/- MEFs. Thus, our study demonstrates that RIPK1 O-GlcNAcylation serves as a checkpoint to suppress necroptotic signaling in erythrocytes.

2023-06-06 | PXD042579 | Pride

Sublethal necroptosis signaling promotes inflammation and liver cancer

Project description:Sublethal necroptosis signaling promotes inflammation and liver cancer

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