TAK1 inhibition leads to RIPK1-dependent apoptosis in immune-activated cancers
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ABSTRACT:
PROVIDER: PRJNA860624 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20334503.fastq.gz | Fastqsanger.gz | |||
| SRR20334504.fastq.gz | Fastqsanger.gz | |||
| SRR20334505.fastq.gz | Fastqsanger.gz | |||
| SRR20334506.fastq.gz | Fastqsanger.gz | |||
| SRR20334507.fastq.gz | Fastqsanger.gz |
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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.
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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.
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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.
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Project description:The pediatric immune deficiency X-linked proliferative disease-2 (XLP-2) is a unique disease, with patients presenting with either hemophagocytic lymphohistiocytosis (HLH) or intestinal bowel disease (IBD). Interestingly, XLP-2 patients display high levels of IL-18 in the serum even while in stable condition, presumably through spontaneous inflammasome activation. Recent data suggests that LPS stimulation can trigger inflammasome activation through a TNFR2/TNF/TNFR1 mediated loop in xiap−/− macrophages. Yet, the direct role TNFR2-specific activation plays in the absence of XIAP is unknown. We found TNFR2-specific activation leads to cell death in xiap−/− myeloid cells, particularly in the absence of the RING domain. RIPK1 kinase activity downstream of TNFR2 resulted in a TNF/TNFR1 cell death, independent of necroptosis. TNFR2-specific activation leads to a similar inflammatory NF-kB driven transcriptional profile as TNFR1 activation with the exception of upregulation of NLRP3 and caspase-11. Activation and upregulation of the canonical inflammasome upon loss of XIAP was mediated by RIPK1 kinase activity and ROS production. While both the inhibition of RIPK1 kinase activity and ROS production reduced cell death, as well as release of IL-1β, the release of IL-18 was not reduced to basal levels. This study supports targeting TNFR2 specifically to reduce IL-18 release in XLP-2 patients and to reduce priming of the inflammasome components.
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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.
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