Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Autophosphorylation at serine 166 regulates RIPK1-mediated cell death and inflammation

ABSTRACT: NEMO-IEC KO mice spontaneously develop chronic colitis characterized by inflammatory gene expression. We characterized the role of RIPK1 auto-phosphorylation in the upregulation of inlflammatory genes in these mice. We used microarray to study the effect of a RIPK1S166A mutation on the gene expression profile in NEMO IEC-KO mice and detect effects on specific inflammatory genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE131855 | GEO | 2020/03/04

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Auto-phosphorylation at serine 166 regulates RIP kinase 1 mediated cell death and inflammation

Project description:Receptor interacting kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces cell death by activating apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signalling remain poorly understood. Here we show that RIPK1 auto-phosphorylation at serine (S) 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans auto-phosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient for the induction of cell death. These results show that S166 auto-phosphorylation licences RIPK1 kinase activity to induce downstream cell death signalling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.

2020-03-23 | PXD014097 | Pride

Expression data from colon samples from FADD IEC-KO (intestinal epithelial cell-knock out) and CASP8 IEC-KO mice in combination with different genetic mutations (Zbp1 -/-, Mlkl -/-, Ripk3 IEC-KO)

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

Expression data from ileum samples from FADD IEC-KO (intestinal epithelial cell-knock out) and CASP8 IEC-KO mice in combination with different genetic mutations (Zbp1 -/-, Mlkl -/-, Ripk3 IEC-KO)

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

Next Generation Sequencing to check the enrichment of RIPK1/BAF on chromatin, RIPK1-dependent chromatin state and RIPK1-dependent transcriptome during inflammatory responses.

Project description:RIPK1 is a master regulator of multiple cell death pathways, including apoptosis and necroptosis, and inflammation. Multiple RIPK1 inhibitors have been advanced into human clinical trials as new therapeutics for human inflammatory and neurodegenerative diseases, including ALS and AD. However, while the mechanism of cytosolic RIPK1 in control of cell death has been extensively investigated, how the activation of RIPK1 may promote transcription of proinflammatory cytokines is unclear as a nuclear function of RIPK1 has not been explored, nor is it clear if and how RIPK1 kinase activity may directly mediate inflammation independent of cell death. Here we show that nuclear RIPK1 is recruited by specific transcription factors and binds to the BAF complex on active enhancers and promoters marked by H3K4me1 and H3K27ac. Nuclear RIPK1 mediates the phosphorylation of SMARCC2, a key component of the BAF complex, to promote chromatin remodeling and the transcription of specific proinflammatory genes. Our results suggest that RIPK1 kinase serves a transcriptional coregulator in nucleus that can transmit extracellular stimuli to BAF complex to modulate the chromatin accessibility and directly regulate the transcription of specific genes involved in mediating inflammatory responses.

2022-07-13 | GSE179018 | GEO

Quantitative Transcriptome Analysis of RIPK1-KO CD4 T cells

Project description:RIPK1 is a key signaling molecule controlling cell death and inflammation through both scaffold and kinase functions of RIPK1. Human RIPK1 deficiency causes immunodeficiency and inflammatory diseases. Here we analyzed the functional roles of RIPK1 in CD4 T cells.

2022-02-27 | GSE197232 | GEO

Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation

Project description:Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a cytosolic protein kinase that regulates multiple inflammatory and cell death pathways. Serine/Threonine phosphorylation of RIPK1 is known to suppress RIPK1 kinase-mediated cell death in the contexts of inflammation, infection and embryogenesis, however, regulation by tyrosine phosphorylation has not been reported. Here, we show that non-receptor tyrosine kinases Janus kinase 1 (JAK1) and SRC are able to phosphorylate RIPK1 at Y384 (Y383 in murine RIPK1), leading to suppression of TNF-induced cell death. Mice bearing a homozygous Ripk1 mutation that prevents tyrosine phosphorylation of RIPK1 (Ripk1Y383F/Y383F), develop systemic inflammation and emergency haematopoiesis. Mechanistically, Ripk1Y383F/Y383F mutation promotes RIPK1 kinase activation and enhances TNF-induced apoptosis and necroptosis, which is partially due to impaired recruitment and activation of MAP kinase-activated protein kinase 2 (MK2). The systemic inflammation and emergency haematopoiesis in Ripk1Y383F/Y383F mice are largely alleviated by RIPK1 kinase inhibition, and prevented by genomic deletions targeted to the upstream pathway (either to Tumor necrosis factor receptor 1 or RIPK3 and Caspase8 simultaneously). In summary, our results demonstrate that tyrosine phosphorylation of RIPK1 is critical for regulating RIPK1 activity to limit cell death and inflammation.

2022-10-12 | PXD036995 | Pride

Genome wide Affymetric Microarray analysis for RIPK1 dependent inflammatory changes in Bone Marrow Derived Macrophages (BMDMs)

Project description:Gene level expression estimate using the Whole Transcript (WT) Assay approach of the Gene 1.0 ST Array System for Mouse. This assay was done to identify the RIPK1-dependent gene expression changes in mouse BMDMs. Cost-effective gene-level analysis based on whole-transcript coverage. We analyzed Bone Marrow Derived Macrophages (BMDMs) under 4 different conditions (Control, LPS, LPS/zVAD, LPS/zVAD/Nec-1) to assess inflammatory changes in RIPK1 kinase dependent manner compared to LPS, LPS/zVAD plus RIPK1 inhibitor Nec-1 and control.

2016-09-07 | E-GEOD-72797 | biostudies-arrayexpress

RIPK1 kinase-dependent gene expression in mouse microglia and astrocytes in vitro

Project description:To determine the role of RIPK1 kinase-dependent transcriptional signaling in microglia and astrocytes, we stimulated cells with RIPK1 kinase-activating stimuli TNF/5z-7 and TNF/Smac/zVAD in the presence or absence of the RIPK1 kinase inhibitor Nec-1s. We identified various genes modulated in a RIPK1 kinase-dependent manner with each stimulation in both microglia and astrocytes, and the main biological pathways were related to an inflammatory and immune response. We identified many cytokines and chemokines upregulated in both microglia and astrocytes upon RIPK1 kinase activation, demonstrating the contribution of RIPK1 kinase signaling to pro-inflammatory responses in microglia and astrocytes

2021-08-12 | GSE154230 | GEO

RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis

Project description:Receptor-interacting protein kinase 1(RIPK1) is a key regulator of inflammation and cell death. Many sites on RIPK1, including serine 25, are phosphorylated to inhibit its kinase activity and cell death. How these inhibitory phosphorylation sites are dephosphorylated is poorly understood. Using a sensitized CRISPR whole genome knockout screen, we discover that protein phosphatase 1 regulatory subunit 3G (PPP1R3G) is required for RIPK1-dependent apoptosis and necroptosis. Mechanistically, PPP1R3G recruits its catalytic subunit protein phosphatase 1 gamma (PP1g) to Complex I to remove inhibitory phosphorylations of RIPK1. A PPP1R3G mutant which does not bind PP1g fails to rescue RIPK1 activation and cell death. Furthermore, chemical prevention of RIPK1 inhibitory phosphorylations or mutation of serine 25 of RIPK1 to alanine largely restores cell death in PPP1R3G-knockout cells. Finally, Ppp1r3g-/- mice are protected from tumor necrosis factor-induced systemic inflammatory response syndrome, confirming the important role of PPP1R3G in regulating apoptosis and necroptosis in vivo.

2021-10-26 | GSE176422 | GEO

SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation

Project description:The mechanism underlying RIPK1-driven cell death and inflammation, a key process in the progression of nonalcoholic steatohepatitis, remains unclear. Here we identified SENP1, a SUMO-specific protease, as a key endogenous inhibitor of RIPK1. SENP1 is progressively reduced in proportion to NASH severity in patients. Hepatocyte-specific SENP1-knockout mice develop spontaneous NASH-related phenotypes in a RIPK1 kinase-dependent manner. We demonstrate that SENP1 deficiency sensitizes cells to RIPK1 kinase-dependent apoptosis by promoting RIPK1 activation following TNFα stimulation. Mechanistically, SENP1 deSUMOylates RIPK1 in TNF-R1 signaling complex (TNF-RSC), keeping RIPK1 in check. Loss of SENP1 leads to SUMOylation of RIPK1, which re-orchestrates TNF-RSC and modulates the ubiquitination patterns and activity of RIPK1. Notably, genetic inhibition of RIPK1 effectively reverses disease progression in hepatocyte-specific SENP1-knockout male mice with high-fat-diet-induced nonalcoholic fatty liver. We propose that deSUMOylation of RIPK1 by SENP1 provides a pathophysiologically relevant cell death-restricting checkpoint that modulates RIPK1 activation in the pathogenesis of nonalcoholic steatohepatitis.

2022-10-20 | GSE193509 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data