CASP8 C362A KI MLKL KO e16.5 intestine RNAseq
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA516934 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8485080.fastq.gz | Fastqsanger.gz | |||
| SRR8485090.fastq.gz | Fastqsanger.gz | |||
| SRR8485081.fastq.gz | Fastqsanger.gz | |||
| SRR8485082.fastq.gz | Fastqsanger.gz | |||
| SRR8485083.fastq.gz | Fastqsanger.gz |
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Project description:Caspase-8 is a protease with both pro-death and pro-survival functions: it is required for apoptosis induced by death receptors such as TNFR1 (tumor necrosis factor receptor 1) 1, and it has a critical role in suppressing necroptosis mediated by the kinase RIPK3 (receptor interacting protein kinase 3) and the pseudokinase MLKL (mixed lineage kinase-like) 2-4. Mice lacking caspase-8 display MLKL-dependent embryonic lethality 4, as do mice expressing catalytically inactive caspase-8 mutant C362A. However, Casp8C362A/C362A Mlkl-/- mice die in the perinatal period, whereas Casp8-/- Mlkl-/- mice are viable 4, indicating that inactive caspase-8 also has a pro-death scaffolding function. Here we show that inactive caspase-8 activates pyroptosis in MLKL-deficient intestinal epithelial cells around embryonic day 18, triggering the formation of ASC specks. Accordingly, intestinal atrophy and perinatal lethality in Casp8C362A/C362A Mlkl-/- mice was prevented by loss of caspase-1. In transfection studies, inactive caspase-8 mutants C362A or C362S were found in both the triton X-100 insoluble and soluble fractions, whereas wild-type caspase-8 existed only in the soluble fraction. Moreover, inactive caspase-8 shifted co-transfected ASC into the insoluble fraction, whereas wild-type caspase-8 did not. Thus, a defense mechanism is revealed that would allow intestinal epithelial cell death in the face of pathogens expressing virulence factors to inhibit caspase-8-dependent apoptosis and necroptosis.
2019-09-20 | GSE125625 | GEO
Project description:Caspase-8 is a protease with both pro-death and pro-survival functions: it is required for apoptosis induced by death receptors such as TNFR1 (tumour necrosis factor receptor 1), and it has a critical role in suppressing necroptosis mediated by the kinase RIPK3 (receptor interacting protein kinase 3) and the pseudokinase MLKL (mixed lineage kinase-like). Mice lacking caspase-8 display MLKL-dependent embryonic lethality, as do mice expressing catalytically inactive caspase-8 mutant C362A. However, Casp8C362A/C362A Mlkl-/- mice die in the perinatal period, whereas Casp8-/- Mlkl-/- mice are viable, indicating that inactive caspase-8 also has a pro-death scaffolding function. Here we show that caspase-8 C362A triggers ASC speck formation and caspase-1-dependent pyroptosis in MLKL-deficient intestinal epithelial cells (IECs) around embryonic day 18. Pyroptosis contributed to the perinatal lethal phenotype because a number of Casp8 C362A/C362A Mlkl-/- Casp1-/- mice survived beyond weaning. Transfection studies suggested inactive caspase-8 adopts a distinct conformation to wild-type caspase-8, enabling it to engage the caspase-1 adaptor ASC. Wild-type caspase-8 was found in the Triton X-100 soluble fraction, whereas wild-type caspase-8 inhibited with the pan-caspase inhibitor emricasan, or inactive caspase-8 mutant C362A, were detected in the insoluble fraction. Moreover, inhibited or inactive caspase-8 shifted ASC into the insoluble fraction. Perinatal lethality was recapitulated when expression of caspase-8 C362A was restricted to IECs, but intriguingly, only in the absence of MLKL. Hence, unanticipated plasticity in death pathways is revealed such that IECs can undergo caspase-1-dependent death when caspase-8-dependent apoptosis and MLKL-dependent necroptosis are inhibited.
2019-09-20 | GSE132133 | GEO
Project description:Single cell RNA-seq of intestine from E18.5 Mlkl -/- and Casp8 C362A/C362A Mlkl -/- embryos
| PRJNA546000 | ENA
Project description:FADD-IEC KO and CASP8 IEC-KO mice spontaneously develop chronic ileitis charcterized by inflammatory gene expression. We characterized the role of MLKL, RIPK3, ZBP1, in the upregulation of inlflammatory genes in these mice. We used microarray to study the effect of MLKL, RIPK3 and ZBP1 on the gene expression profile in FADD IEC-KO and/or CASP8 IEC-KO mice and detect effects on specific inflammatory genes.
2020-05-01 | GSE137280 | GEO
Project description:FADD-IEC KO and CASP8 IEC-KO mice spontaneously develop chronic colitis charcterized by inflammatory gene expression. We characterized the role of MLKL, RIPK3, ZBP1, in the upregulation of inlflammatory genes in these mice. We used microarray to study the effect of MLKL, RIPK3 and ZBP1 on the gene expression profile in FADD IEC-KO and/or CASP8 IEC-KO mice and detect effects on specific inflammatory genes.
2020-05-01 | GSE137281 | GEO
Project description:Necroptosis is a lytic form of cell death that is mediated by the kinase RIPK3 and the pseudokinase MLKL when caspase-8 is inhibited downstream of death receptors, toll-like receptor 3 (TLR3), TLR4, and the intracellular Z-form nucleic acid sensor ZBP1. Oligomerization and activation of RIPK3 is driven by interactions with the kinase RIPK1, the TLR adaptor TRIF, or ZBP1. In this study, we use immunohistochemistry (IHC) and in situ hybridization (ISH) assays to generate a tissue atlas characterizing RIPK1, RIPK3, Mlkl, and ZBP1 expression in mouse tissues. RIPK1, RIPK3, and Mlkl were co-expressed in most immune cell populations, endothelial cells, and many mucosal epithelia. ZBP1 was expressed in many immune populations, but had more variable expression in epithelia compared to RIPK1, RIPK3, and Mlkl. Intriguingly, expression of ZBP1 was elevated in Casp8-/- Tnfr1-/- embryos prior to their succumbing to aberrant necroptosis around embryonic day 15. ZBP1 contributed to this embryonic lethality because rare Casp8-/- Tnfr1-/- Zbp1-/- mice survived until after birth. Necroptosis mediated by TRIF contributed to the demise of Casp8-/- Tnfr1-/- Zbp1-/- pups in the perinatal period. Of note, Casp8-/- Tnfr1-/- Trif-/- Zbp1-/- mice exhibited autoinflammation and morbidity, typically within 5-7 weeks of being born, which is not seen in Casp8-/- Ripk1-/- Trif-/- Zbp1-/-, Casp8-/- Ripk3-/-, or Casp8-/- Mlkl-/- mice. Therefore, after birth, loss of caspase-8 probably unleashes RIPK1-dependent necroptosis driven by death receptors other than TNFR1.
2024-04-01 | GSE254754 | GEO
Project description:Single-cell RNA seq of mouse proximal small intestine at E16.5
| PRJEB31401 | ENA
Project description:OBJECTIVES: To detect the expression levels of MLKL and p-MLKL, and explore its potential roles in inflammatory cell infiltration, angiogenesis, and bone destruction, in human and mouse periapical lesions. METHODS: Forty-six human periapical tissues, including periapical granulomas (PGs, n =26), radicular cysts (RCs, n =20), and eight healthy control tissues were collected. Samples were fixed and analyzed by HE staining, RNA-Seq, western blot, and immunohistochemical staining. A periapical lesion mouse model was induced by pulp exposure in the first lower molars of 15 C57BL/6J mice. After lesion induction, the mice were sacrificed on days 0, 21, and 35. Mandibles were harvested for microcomputed tomography scanning, histologic observation, immunohistochemistry, enzyme histochemistry, and double immunofluorescence analysis. Double immunofluorescence was utilized to assess the colocalization of phosphorylated MLKL (p-MLKL) with CD34, matrix metalloproteinase-9 (MMP-9), and Cathepsin K (CTSK) in human and mouse periapical lesions. RESULTS: RNA-Seq analysis showed that, in comparison with healthy gingiva tissues, MLKL was more significantly upregulated in periapical lesions (P-value < 0.05). Immunohistochemistry staining showed that, MLKL and p-MLKL were significantly overexpressed in the RC and PG groups compared with the control group (P-value < 0.05). However, the difference between the RC and PG groups was insignificant (P-value > 0.05). p-MLKL-positive cells were mainly lymphocytes, epithelial cells, and endothelial cells around the vascular wall. In mouse periapical lesions, the expression levels of p-MLKL were positively correlated with the bone defect area and tartrate-resistant acid phosphatase-positive (TRAP+) cell amounts (R2=0.4108, P-value < 0.05; R2=0.5668, P-value < 0.05, respectively). The double-labeling analysis showed that p-MLKL colocalized with CD34 and MMP-9 in human samples, and with CTSK adjacent to the bone in mouse periapical lesions. CONCLUSION: MLKL and p-MLKL were overexpressed in human periapical lesions. p-MLKL exhibited a close relationship with angiogenesis and alveolar bone resorption.
2024-10-24 | GSE246108 | GEO
Project description:ATAC-seq on embryonic e16.5 mouse intestine For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODE_Data_Use_Policy_for_External_Users_03-07-14.pdf
2021-04-22 | GSE173025 | GEO
Project description:Mixed lineage kinase domain-like (MLKL) is the executioner in the caspase 8-independent form of programmed cell death called necroptosis. Once Receptor Interacting serine/threonine Protein Kinase 3 (RIPK3) is activated by upstream cell death signals, it phosphorylates MLKL and triggers the oligomerization and membrane translocation required for MLKL induced membrane disruption. Besides phosphorylation, MLKL also undergoes ubiquitylation during the early stages of necroptosis, yet neither the mechanism nor the significance of this event has been demonstrated. Here we show that necroptosis-specific, multi-mono-ubiquitylation of MLKL occurs on biological membranes, and requires its activation and oligomerisation. Inactive MLKL mutants recruited to membranes during necroptosis are ubiquitylated but this results in their proteasome and lysosome dependent turnover. We identified several ubiquitylated lysines however mutation of these did not affect MLKL ubiquitylation in response to a necroptotic stimulus.
2021-04-28 | PXD015537 | Pride