Notch reprograms mitochondrial metabolism for macrophage proinflammatory activation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE65151 | GEO | 2017/08/29
SECONDARY ACCESSION(S): PRJNA273278
REPOSITORIES: GEO
Similar Datasets
Project description: Not available
| S-EPMC4396469 | biostudies-literature
Project description:Senescence, a persistent form of cell cycle arrest, is often associated with a diverse secretome, which provides complex downstream functionality for senescent cells within the tissue microenvironment. We show that oncogene-induced senescence (OIS) is accompanied by a dynamic fluctuation of NOTCH1 activity, which drives a TGF-β-rich secretome, whilst suppressing the senescence-associated pro-inflammatory secretome through inhibition of C/EBPβ. NOTCH1 and NOTCH1-driven TGF-β contribute to ‘lateral induction of senescence’ through a juxtacrine NOTCH-JAG1 pathway. In addition, NOTCH1 inhibition during senescence facilitates upregulation of pro-inflammatory cytokines, promoting lymphocyte recruitment and senescence surveillance in vivo. Because enforced activation of NOTCH1 signalling confers a near mutually exclusive secretory profile compared to typical senescence, our data collectively indicate that the dynamic alteration of NOTCH1 activity during senescence dictates a functional balance between these two distinct secretomes: one representing TGF-β and the other pro-inflammatory cytokines, highlighting that NOTCH1 is a temporospatial controller of secretome composition.
2016-08-03 | PXD004168 | Pride
Project description:G1P3 (IFI6) was associated with poor distance metastasis free survival (DMFS) in breast cancer cases. Therefore, we tested the hypothesis that G1P3-induced mitochondrial redox deregulation confers metastatic potentials in breast cancer cells. Our results demonstrate that coordinated action of multiple pathways elicited by G1P3-induced mtROS augment actin-containing migratory structures to promote breast cancer cell migration and invasion Comparative network analysis identified upregulation of antioxidant, acin remodeling, and EMT networks in G1P3 overexpressing MCF-7 cells.
2018-05-24 | GSE113792 | GEO
Project description:NOTCH1 is a transmembrane receptor that initiates the Notch signaling pathway involved in embryonic development and maintenance of adult tissue homeostasis. The extracellular part of NOTCH1 is composed largely of EGF-like domains (EGFs) many of which can be O-fucosylated by protein O-fucosyltransferase 1 (POFUT1). O-fucosylation of NOTCH1 is necessary for its function. The Notch pathway is deregulated in many cancers, and alteration of POFUT1 has been reported in some cancers. Using the Biomuta and COSMIC databases, we selected 9 NOTCH1 variants that could cause a change in O-fucosylation of key EGFs. Cell-based N1 signaling assays, Notch ligand-binding assays and cell surface N1 analysis were used to determine the effect of each mutation on Notch activation. Then mass spectral glycoproteomic site mapping was used to identify alterations in the O-fucosylation of EGFs containing the selected mutation. One of the variants had few effects, two lead to a gain of function (GOF) and six to a loss of function (LOF). Most GOF and LOF could be associated with a change in O-fucosylation. Finally, by comparing our results with known NOTCH1 alterations in cancers from which our mutations originated, we were able to establish a correlation between our results and the known GOF or LOF of NOTCH1 in these cancers. This study shows that point mutations in NOTCH1 can lead to alterations in O-fucosylation that deregulate the Notch pathway and be associated with cancer processes.
2022-10-21 | PXD036345 | Pride
Project description:The Notch signaling system links cellular fate to that of its neighbors, driving proliferation, apoptosis, and cell differentiation in metazoan organisms, whereas dysfunction leads to debilitating developmental disorders and cancers. Here we probe the molecular architecture of mammalian Notch1 full ectodomain in complex with the canonical ligand Jagged1 using cross-linking mass spectrometry (XL-MS). Our data reveals that three Jagged1 sites, C2-epidermal growth factor (EGF) 1, EGF10 and cysteine-rich domain (CRD), are in proximity to the Notch1 negative regulatory region (NRR) in the Notch1-Jagged1 full ectodomain complex. We verified direct interactions and identified additional interacting regions by quantitative-binding experiments. In addition, XL-MS and structural analysis reveal Notch1 and Jagged1 ectodomain intramolecular interactions and structural flexibility that support the formation of backfolded architectures. Together the data suggest a direct and intricate role for the different extracellular regions of Notch1 and Jagged1 in the activation and regulation of Notch1 signaling.
2021-07-08 | PXD023072 | Pride
Project description:Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria.
2021-04-04 | GSE169729 | GEO
Project description:Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria.
2021-04-04 | GSE169728 | GEO
Project description:Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria.
2021-04-04 | GSE169727 | GEO
Project description:Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria.
2021-04-04 | GSE169730 | GEO
Project description:We screened RNAseq results from RAW 264.7 macrophages for previous empirically-defined M2 genes in the whole transcriptome that followed the Arg1 pattern of up-regulation by β-adrenergic-signaling with inhibition by Cebpb gene knockdown. We also screened RAW 264.7 macrophages for empirically-defined M1 genes that exhibited the orthogonal pattern of Arg1 regulation (i.e., down-regulation by β-adrenergic signaling, with rescue of this effect by Cebpb knockdown).
2019-05-08 | GSE119707 | GEO