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OGT controls mammalian cell viability by regulating the proteasome/mTOR/mitochondrial axis

ABSTRACT: TMT-based proteomic and phosphoproteomic analysis of mouse embryonic stem cells upon deletion of Ogt.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Anjana Rao

PROVIDER: MSV000088393 | MassIVE | Tue Nov 16 10:21:00 GMT 2021

REPOSITORIES: MassIVE

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OGT controls mammalian cell viability by regulating the proteasome/mTOR/ mitochondrial axis.

Li Xiang X Yue Xiaojing X Sepulveda Hugo H Burt Rajan A RA Scott David A DA A Carr Steven S A Myers Samuel S Rao Anjana A

Proceedings of the National Academy of Sciences of the United States of America 20230110 3

O-GlcNAc transferase (OGT) modifies serine and threonine residues on nuclear and cytosolic proteins with O-linked N-acetylglucosamine (GlcNAc). OGT is essential for mammalian cell viability, but the underlying mechanisms are still enigmatic. We performed a genome-wide CRISPR-Cas9 screen in mouse embryonic stem cells (mESCs) to identify candidates whose depletion rescued the block in cell proliferation induced by OGT deficiency. We show that the block in cell proliferation in OGT-de ...[more]

PMID: 36626549

Similar Datasets

OGT controls mammalian cell viability by regulating the proteasome/mTOR/ mitochondrial axis.

Project description:O-GlcNAc transferase (OGT) modifies serine and threonine residues on nuclear and cytosolic proteins with O-linked N-acetylglucosamine (GlcNAc). OGT is essential for mammalian cell viability, but the underlying mechanisms are still enigmatic. We performed a genome-wide CRISPR-Cas9 screen in mouse embryonic stem cells (mESCs) to identify candidates whose depletion rescued the block in cell proliferation induced by OGT deficiency. We show that the block in cell proliferation in OGT-deficient cells stems from mitochondrial dysfunction secondary to mTOR (mechanistic target of rapamycin) hyperactivation. In normal cells, OGT maintains low mTOR activity and mitochondrial fitness through suppression of proteasome activity; in the absence of OGT, increased proteasome activity results in increased steady-state amino acid levels, which in turn promote mTOR lysosomal translocation and activation, and increased oxidative phosphorylation. mTOR activation in OGT-deficient mESCs was confirmed by an independent phospho-proteomic screen. Our study highlights a unique series of events whereby OGT regulates the proteasome/ mTOR/ mitochondrial axis in a manner that maintains homeostasis of intracellular amino acid levels, mitochondrial fitness, and cell viability. A similar mechanism operates in CD8+ T cells, indicating its generality across mammalian cell types. Manipulating OGT activity may have therapeutic potential in diseases in which this signaling pathway is impaired.

| S-EPMC9934350 | biostudies-literature

The casein kinase 2-nrf1 axis controls the clearance of ubiquitinated proteins by regulating proteasome gene expression.

Project description:Impairment of the ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of human diseases, including neurodegenerative disorders. Thus, stimulating proteasome activity is a promising strategy to ameliorate these age-related diseases. Here we show that the protein kinase casein kinase 2 (CK2) regulates the transcriptional activity of Nrf1 to control the expression of the proteasome genes and thus the clearance of ubiquitinated proteins. We identify CK2 as an Nrf1-binding protein and find that the knockdown of CK2 enhances the Nrf1-dependent expression of the proteasome subunit genes. Real-time monitoring of proteasome activity reveals that CK2 knockdown alleviates the accumulation of ubiquitinated proteins upon proteasome inhibition. Furthermore, we identify Ser 497 of Nrf1 as the CK2 phosphorylation site and demonstrate that its alanine substitution (S497A) augments the transcriptional activity of Nrf1 and mitigates proteasome dysfunction and the formation of p62-positive juxtanuclear inclusion bodies upon proteasome inhibition. These results indicate that the CK2-mediated phosphorylation of Nrf1 suppresses the proteasome gene expression and activity and thus suggest that the CK2-Nrf1 axis is a potential therapeutic target for diseases associated with UPS impairment.

| S-EPMC3753846 | biostudies-other

Mitochondrial dynamics controls anti-tumour innate immunity by regulating CHIP-IRF1 axis stability.

Project description:Macrophages, dendritic cells and other innate immune cells are involved in inflammation and host defense against infection. Metabolic shifts in mitochondrial dynamics may be involved in Toll-like receptor agonist-mediated inflammatory responses and immune cell polarization. However, whether the mitochondrial morphology in myeloid immune cells affects anti-tumor immunity is unclear. Here we show that FAM73b, a mitochondrial outer membrane protein, has a pivotal function in Toll-like receptor-regulated mitochondrial morphology switching from fusion to fission. Switching to mitochondrial fission via ablation of Fam73b (also known as Miga2) promotes IL-12 production. In tumor-associated macrophages, this switch results in T-cell activation and enhances anti-tumor immunity. We also show that the mitochondrial morphology affects Parkin expression and its recruitment to mitochondria. Parkin controls the stability of the downstream CHIP-IRF1 axis through proteolysis. Our findings identify mechanisms associated with mitochondrial dynamics that control anti-tumor immune responses and that are potential targets for cancer immunotherapy.

| S-EPMC5703766 | biostudies-literature

The mTOR pathway negatively controls ATM by up-regulating miRNAs.

Project description:The ataxia telangiectasia mutated (ATM) checkpoint is the central surveillance system that maintains genome integrity. We found that in the context of childhood sarcoma, mammalian target of rapamycin (mTOR) signaling suppresses ATM by up-regulating miRNAs targeting ATM. Pharmacological inhibition or genetic down-regulation of the mTOR pathway resulted in increase of ATM mRNA and protein both in mouse sarcoma xenografts and cultured cells. mTOR Complex 1 (mTORC1) suppresses ATM via S6K1/2 signaling pathways. microRNA-18a and microRNA-421, both of which target ATM, are positively controlled by mTOR signaling. Our findings have identified a negative feedback loop for the signaling between ATM and mTOR pathways and suggest that oncogenic growth signals may promote tumorigenesis by dampening the ATM checkpoint.

| S-EPMC3718104 | biostudies-literature

mTOR controls ovarian follicle growth by regulating granulosa cell proliferation.

Project description:We have shown that inhibition of mTOR in granulosa cells and ovarian follicles results in compromised granulosa proliferation and reduced follicle growth. Further analysis here using spontaneously immortalized rat granulosa cells has revealed that mTOR pathway activity is enhanced during M-phase of the cell cycle. mTOR specific phosphorylation of p70S6 kinase and 4E-BP, and expression of Raptor are all enhanced during M-phase. The predominant effect of mTOR inhibition by the specific inhibitor Rapamycin (RAP) was a dose-responsive arrest in the G1 cell cycle stage. The fraction of granulosa cells that continued to divide in the presence of RAP exhibited a dose-dependent increase in aberrant mitotic figures known as anaphase bridges. Strikingly, estradiol consistently decreased the incidence of aberrant mitotic figures. In mice treated with RAP, the mitotic index was reduced compared to controls, and a similar increase in aberrant mitotic events was noted. RAP injected during a superovulation regime resulted in a dose-dependent reduction in the numbers of eggs ovulated. Implications for the real-time regulation of follicle growth and dominance, including the consequences of increased numbers of aneuploid granulosa cells, are discussed.

| S-EPMC3130037 | biostudies-literature

Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth

Project description:The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer.

2020-06-29 | MTBLS1764 | MetaboLights

Calcium signaling controls pathogenic Th17 cell-mediated inflammation by regulating mitochondrial metabolism

Project description:Pathogenic Th17 cells play an important role in many autoimmune and inflammatory diseases. Their function is dependent on signaling through the T cell receptor (TCR) and cytokines that activate the transcription factor signal transducer and activator of transcription 3 (STAT3). TCR engagement activates stromal interaction molecule 1 (STIM1) and calcium (Ca2+) influx through the Ca2+ release-activated Ca2+ (CRAC) channel. We here show that deletion of STIM1 and Ca2+ influx in T cells expressing a hyperactive form of STAT3 (STAT3C) attenuates pathogenic Th17 cell function and multiorgan inflammation associated with STAT3C expression. Deletion of STIM1 in pathogenic Th17 cells impairs the expression of nuclear encoded mitochondrial electron transport chain genes and oxidative phosphorylation (OXPHOS) but enhances reactive oxygen species (ROS) production. Deletion of STIM1 or inhibition of OXPHOS is associated with impaired Th17 cell function and a non-pathogenic Th17 gene expression signature. Our findings establish STIM1 and Ca2+ signals as a critical regulator of OXPHOS and oxidative stress in pathogenic Th17 cells and multiorgan inflammation.

2019-01-17 | GSE125204 | GEO

Prominin-1-Radixin Axis controls hepatic gluconeogenesis by regulating PKA activity

Project description:Prominin-1 (Prom1) is a major cell surface marker of cancer stem cells, but its physiological functions in the liver have not been elucidated. We analyzed the levels of mRNA transcripts in serum-starved primary WT (Prom1+/+) and KO (Prom1-/-) mouse hepatocytes using RNA-sequencing (RNA-seq) data, and found that CREB target genes were down-regulated. This initial observation led us to determine that Prom1 deficiency inhibited cAMP response element binding protein (CREB) activation and gluconeogenesis, but not cyclic AMP (cAMP) accumulation, in glucagon-, epinephrine-, or forskolin-treated liver tissues and primary hepatocytes, and mitigated glucagon-induced hyperglycemia. Because Prom1 interacted with radixin, Prom1 deficiency prevented radixin from localizing to the plasma membrane. Moreover, systemic adenoviral knockdown of radixin inhibited CREB activation and gluconeogenesis in glucagon-treated liver tissues and primary hepatocytes, and mitigated glucagon-elicited hyperglycemia. Based on these results, we conclude that Prom1 regulates hepatic PKA signaling via radixin functioning as an A kinase-anchored protein (AKAP).

| S-SCDT-EMBOR-2019-49416-T | biostudies-other

EGFR controls bone development by negatively regulating mTOR-signaling during osteoblast differentiation.

Project description:Mice deficient in epidermal growth factor receptor (Egfr-/- mice) are growth retarded and exhibit severe bone defects that are poorly understood. Here we show that EGFR-deficient mice are osteopenic and display impaired endochondral and intramembranous ossification resulting in irregular mineralization of their bones. This phenotype is recapitulated in mice lacking EGFR exclusively in osteoblasts, but not in mice lacking EGFR in osteoclasts indicating that osteoblasts are responsible for the bone phenotype. Experiments are presented demonstrating that signaling via EGFR stimulates osteoblast proliferation and inhibits their differentiation by suppression of the IGF-1R/mTOR-pathway via ERK1/2-dependent up-regulation of IGFBP-3. Osteoblasts from Egfr-/- mice show increased levels of IGF-1R and hyperactivation of mTOR-pathway proteins, including enhanced phosphorylation of 4E-BP1 and S6. The same changes are also seen in Egfr-/- bones. Importantly, pharmacological inhibition of mTOR with rapamycin decreases osteoblasts differentiation as well as rescues the low bone mass phenotype of Egfr-/- fetuses. Our results demonstrate that suppression of the IGF-1R/mTOR-pathway by EGFR/ERK/IGFBP-3 signaling is necessary for balanced osteoblast maturation providing a mechanism for the skeletal phenotype observed in EGFR-deficient mice.

| S-EPMC5988706 | biostudies-literature

A mammalian-specific Alex3/Galphaq protein complex regulating mitochondrial dynamics, dendritic complexity, and neuronal survival

Project description:Immunoprecipitation of GNAQ protein by immunoprecipitation with two different antibodies from Santa Cruz Biotechnology (C-19 and E-17) in isolated mitochondria from different cell lines. The cell lines used include: Mouse embryonic fibroblasts (MEF) wild-type (WT), GNAQ knockout (KO) and knockout expressing GNAQ WT (KO_Gq). NIH3T3 cells were also used.

2023-11-04 | MSV000093301 | MassIVE

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