Ontology highlight
ABSTRACT:
PROVIDER: PRJNA429329 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6456272_1.fastq.gz | Fastqsanger.gz | |||
| SRR6456272_2.fastq.gz | Fastqsanger.gz | |||
| SRR6456273_1.fastq.gz | Fastqsanger.gz | |||
| SRR6456273_2.fastq.gz | Fastqsanger.gz | |||
| SRR6456274_1.fastq.gz | Fastqsanger.gz |
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Project description:Caspase-8 is a critical regulator of apoptosis, programmed necrosis, and inflammatory gene expression. Caspase-8 is necessary for optimal transcription of inflammatory and antimicrobial host defense genes, including Il12 and Il1b. While the mechanisms of caspase-8-mediated control of apoptosis and programmed necrosis are well-described, how caspase-8 controls inflammatory gene expression is less clear. We show that caspase-8 is necessary for optimal nuclear translocation of the NF-κB family member c-Rel, and consequently, for recruitment of c-Rel to caspase-8-dependent gene promoters. Furthermore, caspase-8 deficiency led to an inability to control acute Toxoplasma gondii infection. These findings provide new insight into how caspase-8 contributes to inflammatory gene expression and host defense.
2019-05-15 | GSE131171 | GEO
Project description:This study demonstrates that TS5-p45 induces endothelial cell (EC) apoptosis in a caspase-dependent manner via its cell surface receptor Nucleolin (NCL). To unravel how this apoptosis mechanism is induced in ECs, we performed RNA-seq using TS5-p45-treated ECs. Transcriptional changes under TS5-p45 treatment was further evaluated to highlight some of the caspase-dependent apoptosis-inducing and -suppressing genes which are altered in favor of apoptosis.
2022-03-02 | GSE191049 | 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:IRF2 regulates macrophages apoptosis through a STAT1/3 and Caspase-1-dependent mechanism
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Project description:A synthetic analog of sphingosine named FTY720 (Fingolimod), phosphorylated by sphingosine kinase-2, interacts with sphingosine-1-phosphate (S1P) receptors expressed on various cells. FTY720 suppresses the disease activity of multiple sclerosis (MS) chiefly by inhibiting S1P-dependent egress of autoreactive T lymphocytes from secondary lymphoid organs, and possibly by exerting anti-inflammmatory and neuroprotective effects directly on brain cells. However, at present, biological effects of FTY720 on human microglia are largely unknown. We studied FTY720-mediated apoptosis of a human microglia cell line HMO6. The exposure of HMO6 cells to non-phosphorylated FTY720 (FTY720-non-P) induced apoptosis in a dose-dependent manner with IC50 of 10.6±2.0 microM, accompanied by the cleavage of caspase-7 and caspase-3 but not of caspase-9. The apoptosis was inhibited by Z-DQMD-FMK, a caspase-3 inhibitor, but not by Pertussis toxin, a Gi protein inhibitor, suramin, a S1P3/S1P5 inhibitor, or W123, a S1P1 competitive antagonist, although HMO6 expressed S1P1, S1P2, and S1P3. Furthermore, both phosphorylated FTY720 (FTY720-P) and SEW2871, a S1P1 selective agonist did not induce apoptosis of HMO6. Genome-wide gene expression profiling and molecular network analysis indicated activation of transcriptional regulation by sterol regulatory element-binding protein (SREBP) in FTY720-non-P-treated HMO6 cells. Western blot verified activation of SREBP2 in these cells, and apoptosis was enhanced by pretreatment with simvastatin, an activator of SREBP2, and by overexpression of the N-terminal fragment of SREBP2. These observations suggest that FTY720-non-P-induced apoptosis of HMO6 human microglia is independent of S1P receptor binding, and positively regulated by the SREBP2-dependent proapoptotic signaling pathway.
2011-04-16 | GSE28642 | 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 (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:A synthetic analog of sphingosine named FTY720 (Fingolimod), phosphorylated by sphingosine kinase-2, interacts with sphingosine-1-phosphate (S1P) receptors expressed on various cells. FTY720 suppresses the disease activity of multiple sclerosis (MS) chiefly by inhibiting S1P-dependent egress of autoreactive T lymphocytes from secondary lymphoid organs, and possibly by exerting anti-inflammmatory and neuroprotective effects directly on brain cells. However, at present, biological effects of FTY720 on human microglia are largely unknown. We studied FTY720-mediated apoptosis of a human microglia cell line HMO6. The exposure of HMO6 cells to non-phosphorylated FTY720 (FTY720-non-P) induced apoptosis in a dose-dependent manner with IC50 of 10.6±2.0 microM, accompanied by the cleavage of caspase-7 and caspase-3 but not of caspase-9. The apoptosis was inhibited by Z-DQMD-FMK, a caspase-3 inhibitor, but not by Pertussis toxin, a Gi protein inhibitor, suramin, a S1P3/S1P5 inhibitor, or W123, a S1P1 competitive antagonist, although HMO6 expressed S1P1, S1P2, and S1P3. Furthermore, both phosphorylated FTY720 (FTY720-P) and SEW2871, a S1P1 selective agonist did not induce apoptosis of HMO6. Genome-wide gene expression profiling and molecular network analysis indicated activation of transcriptional regulation by sterol regulatory element-binding protein (SREBP) in FTY720-non-P-treated HMO6 cells. Western blot verified activation of SREBP2 in these cells, and apoptosis was enhanced by pretreatment with simvastatin, an activator of SREBP2, and by overexpression of the N-terminal fragment of SREBP2. These observations suggest that FTY720-non-P-induced apoptosis of HMO6 human microglia is independent of S1P receptor binding, and positively regulated by the SREBP2-dependent proapoptotic signaling pathway. The HMO6 cell line was established by immortalizing cultured microglia isolated from human embryonic telencephalon tissues with a retroviral vector PASK1.2 encoding v-myc oncogene (Nagai et al. Neurobiol. Dis. 8: 1057-1068, 2001). HMO6 cells express the markers of the microglia/macrophage lineage cells, including CD11b, CD68, CD86, HLA-ABC, HLA-DR, and ricinus communis agglutinin lectin-1 (RCA), serving as a model of human microglia both in vitro and in vivo. The cells were exposed for 2 hours to 10 microM FTY720-non-P dissolved in dimethyl sulfoxide (DMSO) or ethanol or exposed to the vehicle.
2011-04-16 | E-GEOD-28642 | biostudies-arrayexpress
Project description:This is the standard model described in the article:
Systems analysis of effector caspase activation and its control by X-linked inhibitor of apoptosis protein.
Rehm M, Huber HJ, Dussmann H, Prehn JH.
EMBO J. 2006 Sep 20;25(18):4338-49. Epub 2006 Aug 24.
PMID:16932741, doi:10.1038/sj.emboj.7601295;
Abstract:
Activation of effector caspases is a final step during apoptosis. Single-cell imaging studies have demonstrated that this process may occur as a rapid, all-or-none response, triggering a complete substrate cleavage within 15 min. Based on biochemical data from HeLa cells, we have developed a computational model of apoptosome-dependent caspase activation that was sufficient to remodel the rapid kinetics of effector caspase activation observed in vivo. Sensitivity analyses predicted a critical role for caspase-3-dependent feedback signalling and the X-linked-inhibitor-of-apoptosis-protein (XIAP), but a less prominent role for the XIAP antagonist Smac. Single-cell experiments employing a caspase fluorescence resonance energy transfer substrate verified these model predictions qualitatively and quantitatively. XIAP was predicted to control this all-or-none response, with concentrations as high as 0.15 microM enabling, but concentrations >0.30 microM significantly blocking substrate cleavage. Overexpression of XIAP within these threshold concentrations produced cells showing slow effector caspase activation and submaximal substrate cleavage. Our study supports the hypothesis that high levels of XIAP control caspase activation and substrate cleavage, and may promote apoptosis resistance and sublethal caspase activation in vivo.
This model is slightly altered from the description in the article. Cytochrome C and SMAC release from the mitochondrion is modelled as simple first order kinetics, giving the same form as the (integrated) equations in the supplement of the article. The apoptosome formation is modelled equally - and independent of the Cytochrome C release. The speed is either limited by the Apaf1 or ProCaspase9 concentration, whichever is higher, symbolised via the parameter with the ID apolim.
Also, once the substrate concentration falls below 1 percent, the event Production_Breakdown is triggered, leading to a breakdown of XIAP and procaspase3 production and turning off of the enhanced/proteosomal degradation (degradation rate for reactions 38,39,40,43,44,46,48,50,51 changes from 0.0347 to 0.0058).
Originally created by libAntimony v1.3 (using libSBML 3.4.1)
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2012 The BioModels.net Team.
For more information see the terms of use.
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2024-09-02 | BIOMD0000000256 | BioModels
Project description:Cells are in constant adaptation to environmental changes to insure their proper functioning. When exposed to stresses, cells activate specific pathways to elicit adaptive modifications. Those changes can be mediated by selective modulation of gene and protein expression as well as by post-translational modifications, such as phosphorylation and proteolytic processing. Protein cleavage, as a controlled and limited post-translational modification, is involved in diverse physiological processes such as the maintenance of protein homeostasis, activation of repair pathways, apoptosis and the regulation of proliferation. Here we assessed by quantitative proteomics the proteolytic landscape in two cell lines subjected to low cisplatin concentrations used as a mild non-lethal stress paradigm. This landscape was compared to the one obtained in the same cells stimulated with cisplatin concentrations inducing apoptosis. These analyses were performed in wild-type cells and in cells lacking the two main executioner caspases: caspase-3 and caspase-7. Ninety proteins were found to be cleaved at one or a few sites (discrete cleavage) in low stress conditions compared to four hundred and forty in apoptotic cells. Many of the cleaved proteins in stressed cells were also found to be cleaved in apoptotic conditions. As expected in apoptotic cells, ~80% of the cleavage events were dependent on caspase 3/caspase 7. Strikingly, upon exposure to non-lethal stresses, no discrete cleavage was detected in cells lacking caspase-3 and caspase-7. This indicates that the proteolytic landscape in stressed viable cells fully depends on the activity of executioner caspases. These results suggest that the so-called executioner caspases fulfill important stress adaptive responses distinct from their role in apoptosis.
2021-07-07 | PXD023488 | Pride
Project description:Hydrogen sulfide has been implicated in a large number of physiological processes including cell survival and death, encouraging research into its mechanisms of action and therapeutic potential. Recent studies suggest that the cellular effects of hydrogen sulfide are mediated in part by sulfane sulfur species including persulfides and polysulfides. In the present study, we investigated the apoptosis-modulating effects of polysulfides, in particular, in relation to the caspase cascade that mediates the intrinsic apoptotic pathway. Biochemical analyses revealed that organic or synthetic polysulfides strongly and rapidly inhibited the enzymatic activity of caspase-3, a major effector protease in apoptosis. Enzyme inhibition was attributed to persulfidation of the catalytic cysteine. In apoptotically stimulated HeLa cells, short-term exposure to polysulfides triggered the persulfidation and deactivation of cleaved caspae-3. These effects were antagonized by the thioredoxin/thioredoxin reductase system (Trx/TrxR). Indeed, Trx/TrxR restored the activity of polysulfide-inactivated caspase-3 in vitro, and inhibition of TrxR potentiated polysulfidemediated suppression of caspase-3 activity in situ. We further found that under conditions of low TrxR activity, early cell exposure to polysulfides lead to enhanced persulfidation of initiator caspase-9, resulting in decreased apoptosis. Beyond these observations, we show that the proenzymes, procaspase-3/-9, are basally persulfidated in resting (unstimulated) cells and become depersulfidated during their processing and activation. Inhibition of TrxR attenuated the depersulfidation and activation of caspase-9. Taken together, our results reveal that polysulfides target the caspase-9/3 cascade to suppress cancer cell apoptosis. The findings further suggest that Trx/TrxR-mediated depersulfidation may regulate caspase-dependent cell death.
2020-02-18 | PXD017144 | Pride