Hepatocyte-Specific TAK1 Deficiency Drives RIPK1 Kinase-dependent Inflammation to Promote Liver Fibrosis and Hepatocellular Carcinoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA625978 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Transforming growth factor beta-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death and carcinogenesis. Hepatocyte-specific deletion of TAK1 in Tak1_Hep mice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using kinase dead knock-in D138N mutation in Tak1_Hep mice inhibits the expression of liver tumor biomarkers, liver fibrosis and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single cell RNA-seq, we discover that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2+ macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-non-autonomously, in the development of liver fibrosis and HCC, independent of cell death and compensatory proliferation. We suggest the possibility of inhibiting RIPK1 kinase as a therapeutic strategy for reducing liver fibrosis and HCC development by inhibiting inflammation.
2020-07-08 | GSE148859 | GEO
Project description: Not available
| S-EPMC7322083 | biostudies-literature
Project description:Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. Here we investigate how partial loss-of-function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1-/- mice is dependent on RIPK1 kinase activity. In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show that in Tbk1+/- mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss and behavior deficits, which are blocked upon inhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.
2018-07-04 | GSE116613 | GEO
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
Project description:The effect of ablation of Tak1 gene in the liver was characterized. RNA was extracted from 1-month-old WT and hepatocyte specific TAK1-deleted mice
2014-12-22 | E-GEOD-51962 | biostudies-arrayexpress
Project description:To determine the role of RIPK1 kinase-dependent transcriptional signaling in human fetal-derived astrocytes, we stimulated cells with the RIPK1 kinase-activating stimulus 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 in human astrocytes, and the main biological pathways were related to an interferon signaling and anti-viral response.
2021-08-12 | GSE172027 | GEO
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
Project description:To evaluate the effects of TAK1 inhibition on TGF-beta regulated fibrosis using a novel small molecule inhibitor of TAK1.
2023-05-17 | GSE232435 | GEO
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
Project description:Poor survival and lack of response to current treatment modalities in adult human glioblastomas is attributed to the persistence of a subpopulation of glioma stem cells (GSCs). To identify novel approaches to therapeutically target GSCs, we performed CRISPR/Cas9 knockout screens in GSCs and identified the kinase TAK1 as an important selective survival factor in 50% of the tested GSCs. In sensitive cells, knockout of TAK1 leads to induction of caspase-dependent apoptosis via the RIPK1/Caspase 8/FADD complex due to constitutive, low-level secretion of tumor necrosis factor alpha (TNF-a) and stimulation of TNF receptor 1. Furthermore, we show that expression of genes involved in immune signaling and a mesenchymal signature predict the sensitivity and response of GSCs to TAK1 inhibition. In summary, we have identified TAK1 as a new therapeutic target for mesenchymal GBM and a potential gene signature for selection of patients benefitting from TAK1 targeted therapy.
2023-07-21 | GSE208697 | GEO