Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA304012 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Formation of the Death-Inducing Signalling Complex (DISC) initiates the extrinsic apoptotic signalling cascade. Caspase-8 and its regulator cFLIP control death signalling by binding to the receptor via DISC-bound FADD. By elucidating the function of Caspase-10, a close homologue of caspase-8, we unexpectedly found that caspase-10 negatively regulates caspase-8-mediated cell death signalling in the DISC. We demonstrate that caspase-10 inhibits the activation of caspase-8 independent of cFLIP. Furthermore, we show that caspase-8 does not compete with other tandem DED proteins such as cFLIP or caspase-10 in binding via FADD to the receptor as current models suggest. By utilizing caspase-8 knockout cells, we demonstrate that caspase-8 has to be placed upstream of both cFLIP and caspase-10 in the DISC. We further show that DISC formation and/or stability depends on caspase-8 but is independent from its enzymatic activity. Surprisingly, we identified caspase-10 to rewire DISC-signalling to NF-kB activation and cell survival. Our data are consistent with a model in which caspase-10 and cFLIP co-ordinately regulate caspase-8-mediated cell death signalling.
2016-04-20 | GSE75365 | GEO
Project description:Control of Autophagic Cell Death by Caspase-10 in Multiple Myeloma
| PRJNA188236 | ENA
Project description:We performed a loss-of-function, RNA interference screen to define new therapeutic targets in multiple myeloma, a genetically diverse plasma cell malignancy. Unexpectedly, we discovered that all myeloma lines require caspase-10 for survival, irrespective of their genetic abnormalities. The transcription factor IRF4 induces both caspase-10 and its associated protein cFLIPL in myeloma, generating a protease that does not induce apoptosis but rather blocks an autophagy-dependent cell death pathway. Caspase-10 inhibits autophagy by cleaving the BCL2-interacting protein BCLAF1, itself a strong inducer of autophagy that acts by displacing beclin-1 from BCL2. While myeloma cells require a basal level of autophagy for survival, caspase-10 tempers this response to avoid cell death. Drugs that disrupt this vital balance may have therapeutic potential in myeloma.
2013-03-13 | GSE43878 | GEO
Project description:The loss of functional caspase-10 promotes inflammatory cell death in macrophages and a fibrotic response of hepatic stellate cells, which may affect the pathogenesis of PBC.
2022-12-31 | GSE210070 | GEO
Project description:We performed a loss-of-function, RNA interference screen to define new therapeutic targets in multiple myeloma, a genetically diverse plasma cell malignancy. Unexpectedly, we discovered that all myeloma lines require caspase-10 for survival, irrespective of their genetic abnormalities. The transcription factor IRF4 induces both caspase-10 and its associated protein cFLIPL in myeloma, generating a protease that does not induce apoptosis but rather blocks an autophagy-dependent cell death pathway. Caspase-10 inhibits autophagy by cleaving the BCL2-interacting protein BCLAF1, itself a strong inducer of autophagy that acts by displacing beclin-1 from BCL2. While myeloma cells require a basal level of autophagy for survival, caspase-10 tempers this response to avoid cell death. Drugs that disrupt this vital balance may have therapeutic potential in myeloma. To generate a gene expression signature of caspase 10 signaling in multiple myeloma, cell lines (SKMM1 n=16, KMS12 n=8 and H929 n=12) were transduced with retroviral vectors expressing either shCasp10-2 or shCasp10-3. Similarly, lymphoma cell lines (OCI-Ly7 n=2 and OCI-Ly19 n=2) were transduced and used as a control. Following puromycin selection, shRNA expression was induced for 24 to 120 hours and gene expression was measured, comparing uninduced (Cy3) to induced (Cy5) cells, using lymphochip microarrays. Biological repeats were performed of H929 and SKMM1 samples.
2013-03-13 | E-GEOD-43878 | biostudies-arrayexpress
Project description:The non-canonical caspase-4/5 inflammasome has been only very recently characterized. It is expressed by macrophages, the principal effector cells of the innate immunity system, and is activated by gram-negative bacteria, ER stress, and UV radiation. Activation of this inflammasome results in pyroptosis, inflammatory cell death, and secretion of pro-inflammatory cytokines of the interleukin-1 family. In our model we transfected human primary macrophages with Lipopolysaccharide, a cell wall component of gram-negative bacteria, to simulate bacteria entering the cell and thus activating the caspase-4/5 inflammasome. We then performed high-throughput proteomics to identify proteins secreted during the stimulation. The secretome was separated into two fractions using size-exclusion centrifugation, with a 100 kDa cut-off we enriched extracellular vesicles (EVs) and the flow through was concentrated over 10 kDa to yield the rest-secretome (RS) samples. The EV and RS samples of LPS transfected cells were then compared to untreated cells.
2017-03-29 | MSV000080769 | MassIVE
Project description:The non-canonical caspase-4/5 inflammasome has been only very recently characterized. It is expressed by macrophages, the principal effector cells of the innate immunity system, and is activated by gram-negative bacteria, ER stress, and UV radiation. Activation of this inflammasome results in pyroptosis, inflammatory cell death, and secretion of pro-inflammatory cytokines of the interleukin-1 family. In our model we transfected human primary macrophages with Lipopolysaccharide, a cell wall component of gram-negative bacteria, to simulate bacteria entering the cell and thus activating the caspase-4/5 inflammasome. We then performed high-throughput proteomics to identify proteins secreted during the stimulation. The secretome was separated into two fractions using size-exclusion centrifugation, with a 100 kDa cut-off we enriched extracellular vesicles (EVs) and the flow through was concentrated over 10 kDa to yield the rest-secretome (RS) samples. The EV and RS samples of LPS transfected cells were then compared to untreated cells.
2017-03-07 | PXD005083 | Pride
Project description:Caspase-8 modulates TLR-induced gene transcription, which is only partially dependent on caspase-8 catalytic activity. Moreover, The slow kinetics of IFNγ and LPS-induced BMDM killing offers the possibility that transcriptional responses may contribute to cell death activation. We performed 3' mRNA-sequencing to examine whether caspase-8 might contribute, at least in part, to IFNγ and LPS-triggered macrophage death via its transcriptional role. We found that caspase-8-mediated transcriptional re-programming of BMDMs. Importantly, caspase-8 modulates expression of Bcl-2 family members and inducible nitric oxide synthase (iNOS) to promote activation of the mitochondrial apoptotic effectors, BAX and BAK.
2021-12-15 | GSE161179 | GEO
Project description:We identify spermidine targeting RIPK1, a key regulator of cell death and inflammation, by mediating a new type of posttranslational modification, named acetylhypusination, to inhibit RIPK1-mediated inflammation and cell death.
2023-11-18 | PXD047079 | iProX
Project description:The execution of shock following high dose E. coli lipopolysaccharide (LPS) or bacterial sepsis in mice required pro-apoptotic caspase-8 in addition to pro-pyroptotic caspase-11 and gasdermin d. Hematopoietic cells produced MyD88- and TRIF-dependent inflammatory cytokines sufficient to initiate LPS shock independent of caspase-8 or caspase-11. Both proteases had to be present to support tissue injury, dependent upon TNF and interferon , first observed in the small intestine and later in spleen and thymus. Caspase-11 enhanced the activation of caspase-8 and extrinsic cell death machinery within the lower small intestine. Neither caspase-8 nor caspase-11 was individually sufficient for shock, but collaborated to amplify the inflammatory signals associated with tissue injury. Therefore, combined pyroptotic and apoptotic signaling mediated endotoxemia independent of RIPK1 kinase activity and RIPK3 function. These observations bring to light the relevance of tissue compartmentalization during inflammatory signaling in vivo where cytokines execute diverse cell death pathways and tissue damage.
2018-08-07 | GSE115094 | GEO