Sublethal necroptosis signaling promotes inflammation and liver cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE166875 | GEO | 2023/07/03
REPOSITORIES: GEO
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Project description:Necroptosis and ferroptosis are two pathways of regulated cell death executed in several major cardiovascular and neurological acute and degenerative diseases. While the necroptosis program relies on activation of RIP1, RIP3 kinases and MLKL, ferroptotic death is triggered by 15- Lipoxygenase (15LO) catalyzed oxidation of arachidonoyl- (AA) or adrenoyl- (AdA) phosphatidylethanolamines (PE) controlled by the phosphatidylethanolamine-binding protein 1 (PEBP1). PEBP1 displays “regulatory” promiscuity towards multiple protein partners, including RAF1 kinase. Given a distinct structural homology between RAF1 kinase and RIP3 kinase, we hypothesized that PEBP1 may interact with RIP3 and act as a switch from necroptosis to ferroptosis. Using computational, genetic and redox lipidomics approaches, we show that PEBP1 liberated from RAF1 kinase binds and sterically inhibits RIP3 thus turning-off necroptosis. Highly expressed 15LO may outcompete and bind PEBP1 to promote AA-PE/AdA-PE oxidation and ferroptosis. Using cell- based and animal models, we identified the conditions disrupting PEBP1’s interactions with RAF1 kinase to alternatively bind/inhibit RIP3 kinase or bind/activate 15LO. We further established that PEBP1 knockdown sensitizes cells to RIP3-mediated necroptosis. These newly established regulatory functions of PEBP1 serve multiple and diverse roles across various human disease states.
2020-01-16 | ST001334 | MetabolomicsWorkbench
Project description:The aetiology of bowel inflammatory disease (IBD) is a multifactorial interplay between heredity and environment1-3. Here we report SETDB1, a histone methyltransferase (HMTs) for histone H3 lysine 9 trimethylation (H3K9me3) whose deficiency participates in the pathogenesis of IBD. We found that SETDB1 level decreased in IBD patients and that mice with reduced SETDB1 in intestinal stem cells (ISCs) developed spontaneous terminal ileitis and colitis. SETDB1 safeguards genome stability4, of which the loss in ISCs released repression of endogenous retrovirus (ERVs), the retrovirus-like elements with long repeats that comprise ~8% of genome5. Excessive viral mimicry generated by motivated ERVs triggered Z-DNA-binding protein 1 (ZBP1) dependent necroptosis, which irreversibly disrupted the homeostasis of epithelial barrier and promoted bowel inflammation. Of note, genome instability, reactive ERVs, upregulation of ZBP1 and necroptosis were seen in IBD patients. Pharmaceutic inhibition of RIP3 showed curative effect in SETDB1 deficient mice, suggesting therapy targeting ISC necroptosis may represent a new approach for severe IBD treatment.
2020-01-01 | GSE129173 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with two major biological subtypes, activated B-cell like (ABC) and germinal center B-cell-like (GCB) DLCBL. Self-antigen engagement of B-cell receptors (BCRs) in ABC tumors promotes their clustering in the plasma membrane, thereby initiating chronic active signaling and downstream activation of the pro-survival NF-kB and PI3 kinase pathways. The potential of therapeutics targeting chronic active BCR signaling in ABC DLBCL is highlighted by the frequent response of these tumors to inhibitors of BTK, a kinase that links BCR signaling to NF-kB activation. Here we used genome-wide CRISPR-Cas9 screens to identify regulators of the IRF4, a direct NF-kB target and essential transcription factor in ABC cells. Unexpectedly, inactivation of the oligosaccharyltransferase (OST) complex, which mediates N-linked protein glycosylation, reduced IRF4 expression and NF-kB activity in ABC cells, resulting in cell death. Using functional glycoproteogenomics we linked this phenomenon to defective BCR glycosylation. Pharmacologic inhibition of OST reduced the size and abundance of BCR microclusters in the plasma membrane and blocked their internalization. These reorganized BCRs associated with the inhibitory coreceptor CD22, which attenuated proximal BCR signaling, thereby reducing NF-kB and PI3 kinase activation. OST inhibition also blocked the trafficking of TLR9 to the endolysosomal compartment, preventing its association with the BCR in the My-T-BCR signaling complex that activates NF-kB in ABC cells. In GCB DLBCL, OST inhibition also attenuated constitutive BCR signaling, reducing PI3 kinase signaling and triggering cell death. Our data highlight the therapeutic potential of OST inhibitors for the treatment of diverse B cell malignancies in which constitutive BCR signaling is essential.
2023-04-24 | PXD038951 | Pride
Project description:Necroptosis is a form of regulated necrotic cell death which promotes inflammation. In cells undergoing necroptosis, the activated RIPK1 kinase mediates the formation of RIPK1/RIPK3/MLKL complex to promote MLKL oligomerization and execution of necroptosis. RIPK1 kinase activity also promotes cell-autonomous activation of proinflammatory cytokine production in necroptosis. However, the signaling pathways downstream of RIPK1 kinase in necroptosis and how RIPK1 kinase activation controls inflammatory response induced by necroptosis are still largely unknown. Here we quantitatively measured the temporal dynamics of over 7000 confident phosphosites during necroptosis using mass spectrometry. Our study defined a RIPK1-dependent phosphorylation pattern in late necroptosis that is associated with a proinflammatory component marked by p-S473 TRIM28. We show that the activation of p38 MAPK mediated by oligomerized MLKL promotes the phosphorylation of S473 TRIM28, which in turn mediates inflammation during late necroptosis. Taken together, our study illustrates a mechanism by which p38 MAPK may be activated by oligomerized MLKL to promote inflammation in necroptosis.
2021-04-01 | GSE171214 | GEO
Project description:The aetiology of bowel inflammatory disease (IBD) is a multifactorial interplay between heredity and environment1-3. Here we report SETDB1, a histone methyltransferase (HMTs) for histone H3 lysine 9 trimethylation (H3K9me3) whose deficiency participates in the pathogenesis of IBD. We found that SETDB1 level decreased in IBD patients and that mice with reduced SETDB1 in intestinal stem cells (ISCs) developed spontaneous terminal ileitis and colitis. SETDB1 safeguards genome stability4, of which the loss in ISCs released repression of endogenous retrovirus (ERVs), the retrovirus-like elements with long repeats that comprise ~8% of genome5. Excessive viral mimicry generated by motivated ERVs triggered Z-DNA-binding protein 1 (ZBP1) dependent necroptosis, which irreversibly disrupted the homeostasis of epithelial barrier and promoted bowel inflammation. Of note, genome instability, reactive ERVs, upregulation of ZBP1 and necroptosis were seen in IBD patients. Pharmaceutic inhibition of RIP3 showed curative effect in SETDB1 deficient mice, suggesting therapy targeting ISC necroptosis may represent a new approach for severe IBD treatment.
2020-01-01 | GSE129172 | GEO
Project description:Sublethal necroptosis signaling promotes inflammation and liver cancer
| PRJNA702161 | ENA
Project description:Dynamic control of ubiquitination by deubiquitinating enzymes is essential for almost all biological processes. Ubiquitin-specific peptidase 22 (USP22) is part of the SAGA complex and catalyzes the removal of monoubiquitination from histone H2B, thereby regulating gene transcription. However, novel roles for USP22 have recently emerged, such as tumor development and cell death. Apart from apoptosis, the relevance of USP22 in other programmed cell death pathways still remains unclear. Here, we describe a novel role for USP22 in controlling necroptotic cell death in a variety of tumor cell lines. Loss of USP22 expression significantly delays TNF/Smac mimetic/zVAD.fmk (TBZ)-induced necroptosis, without affecting TNF-mediated NF-B activation or extrinsic apoptosis. Mass-spectrometric ubiquitin remnant profiling identified lysine 518 of Receptor-interacting protein kinase 3 (RIPK3) as USP22-dependent ubiquitination target during necroptosis induction. Mutation of K518 in RIPK3 reduced necroptosisassociated RIPK3 ubiquitination and amplified necrosome formation and necroptotic cell death. In conclusion, we identify a novel role of USP22 in necroptosis and further elucidate the relevance of ubiquitination as crucial regulator of necroptotic cell death.
2021-05-03 | PXD020909 | Pride
Project description:MicroRNAs (miRNAs) are small RNAs that regulate the expression of specific target genes. While deregulated miRNA expression levels have been detected in many tumors, whether miRNA functional impairment is also involved in carcinogenesis remains unknown. We investigated whether deregulation of miRNA machinery components and subsequent functional impairment of miRNAs are involved in hepatocarcinogenesis. Among miRNA-containing ribonucleoprotein complex components, reduced expression of DDX20 was frequently observed in human hepatocellular carcinomas, in which enhanced NF-kB activity is closely linked to carcinogenesis. Because DDX20 normally suppresses NF-kB activity by preferentially regulating the function of the NF-kB suppressing miRNA-140, we hypothesized that impairment of miRNA-140 function may be involved in hepatocarcinogenesis. Dnmt1 was identified as a direct target of miRNA-140, and increased Dnmt1 expression in DDX20-deficient cells hypermethylated the promoters of metallothionein genes, resulting in decreased metallothionein expression leading to enhanced NF-kB activity and hepatocarcinogenesis. MiRNA-140 knockout mice were prone to hepatocarcinogenesis and showed phenomena similar to those of DDX20 deficiency, suggesting that miRNA-140 plays a central role in DDX20 deficiency–related pathogenesis. Conclusion: These results indicate that miRNA-140 acts as a liver tumor suppressor, and that impairment of miRNA-140 function due to a deficiency of DDX20, a miRNA machinery component, could lead to hepatocarcinogenesis. Genome wide DNA methylation profiling of control and DDX20-knockdown HepG2 cells. Bisulphite converted DNA from the 2 samples were hybridised to the Illumina HumanMethylation450 BeadChip.
2012-04-26 | E-GEOD-37633 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) are small RNAs that regulate the expression of specific target genes. While deregulated miRNA expression levels have been detected in many tumors, whether miRNA functional impairment is also involved in carcinogenesis remains unknown. We investigated whether deregulation of miRNA machinery components and subsequent functional impairment of miRNAs are involved in hepatocarcinogenesis. Among miRNA-containing ribonucleoprotein complex components, reduced expression of DDX20 was frequently observed in human hepatocellular carcinomas, in which enhanced NF-kB activity is closely linked to carcinogenesis. Because DDX20 normally suppresses NF-kB activity by preferentially regulating the function of the NF-kB suppressing miRNA-140, we hypothesized that impairment of miRNA-140 function may be involved in hepatocarcinogenesis. Dnmt1 was identified as a direct target of miRNA-140, and increased Dnmt1 expression in DDX20-deficient cells hypermethylated the promoters of metallothionein genes, resulting in decreased metallothionein expression leading to enhanced NF-kB activity and hepatocarcinogenesis. MiRNA-140 knockout mice were prone to hepatocarcinogenesis and showed phenomena similar to those of DDX20 deficiency, suggesting that miRNA-140 plays a central role in DDX20 deficiency–related pathogenesis. Conclusion: These results indicate that miRNA-140 acts as a liver tumor suppressor, and that impairment of miRNA-140 function due to a deficiency of DDX20, a miRNA machinery component, could lead to hepatocarcinogenesis.
2012-04-27 | GSE37633 | GEO
Project description:IKKβ-dependent NF-κB activation is associated with inflammation and tumorigenesis and is critical for innate immunity. Despite risk of immune suppression, pharmacological blockade of IKKβ/NF-κB has been considered as an attractive strategy for treatment of inflammatory diseases and cancer. Unexpectedly, treatment with IKKβ inhibitors caused neutrophilia, which also occurs in mice with inducible IKKβ deletion, termed IkkβΔ mice. IkkβΔ mice show hyperproliferation of granulocyte progenitors and increased neutrophil lifespan. Deletion of IL-1 receptor 1 in IkkβΔ mice restored normal blood cellularity and prevented neutrophil-driven inflammation. However, IkkβΔ/Il-1r1-/- mice, in contrast to IkkβΔ mice, are highly susceptible to bacterial infections indicating that either IKKβ/NF-κB or IL-1R signaling are sufficient for maintaining anti-microbial defenses, but inactivation of both pathways severely compromises innate immunity. Thioglycollate-elicited peritoneal neutrophils were purified from IkkβF/F and IkkβΔ mice using anti-Ly-6G magnetic beads and cultured. Ly-6G+ neutrophils were collected and total RNA was extracted with TRIzol® (Invitrogen) and was purified by RNA micro cleanup Kit (Qiagen). Biotinylated cRNA was synthesized using an RNA Amplification Kit (Ambion) following manufacturer's directions. Biotin-labeled cRNA was hybridized to Illumina Mouse-Ref8 BeadChips (Illumina) and the results were analyzed using BeadStudio v3.1 software. Data analysis and quality control were carried out using Partek® software.
2010-11-12 | E-GEOD-25211 | biostudies-arrayexpress