Autophagy mediates p53 degradation and is essential for human myelopoiesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA925239 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23116616_1.fastq.gz | Fastqsanger.gz | |||
| SRR23116616_2.fastq.gz | Fastqsanger.gz | |||
| SRR23116617_1.fastq.gz | Fastqsanger.gz | |||
| SRR23116617_2.fastq.gz | Fastqsanger.gz | |||
| SRR23116618_1.fastq.gz | Fastqsanger.gz |
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Project description:Emergency myelopoiesis (EM) is critical for immune defense against pathogens, which requires rapid replenishing of mature myeloid cells. The EM process involves a rapid cell cycle switch from the quiescent hematopoietic stem cells (HSCs) to highly proliferative myeloid progenitors (MPs). How this cell cycle switch is regulated remains poorly understood. Here, we reveal that ATG7, a critical autophagy factor is essential for the rapid proliferation of MPs during human myelopoiesis. Peripheral blood (PB) mobilized HSPCs with ATG7 knock-down or HSPCs derived from ATG7-/- human embryonic stem cells (hESCs) exhibit severe defect in proliferation at MP stage during myeloid/granulocytes differentiation. ATG7 deficient MPs show substantially elevated P53 protein and up-regulation of P53 signaling pathway genes. Mechanistically, ATG7 dependent autophagy mediates P53 degradation in lysosome that allows normal proliferation of MPs. Together, we reveal an essential role of autophagy for P53 degradation in cell cycle switch during human myelopoiesis
2023-01-25 | GSE223219 | GEO
Project description:Autophagy is a catabolic membrane trafficking process involved in degradation of cellular constituents through lysosomes, which maintains cell and tissue homeostasis. While much attention has been focused on autophagic turnover of cytoplasmic materials, little is known regarding the role of autophagy in degrading nuclear components. Here we report that autophagy machinery mediates degradation of nuclear lamina in mammalian cells, a process we term laminophagy. The autophagy protein LC3 is present in the nucleus and directly interacts with the nuclear lamina protein Lamin B1, and associates with lamin-associated domains (LADs) on chromatin. This interaction does not downregulate Lamin B1 during starvation, but mediates nuclear lamina degradation upon tumorigenic insults, such as by oncogenic Ras. Laminophagy is achieved by nucleus-to-cytosol transport that delivers Lamin B1 to lysosome for degradation. Inhibiting autophagy or LC3-Lamin B1 interaction prevents oncogenic Ras-induced Lamin B1 loss and delays oncogene-induced cell cycle arrest. Our study unveils a role of autophagy in degrading nuclear materials, and suggests laminophagy as a guarding mechanism protecting cells from tumorigenesis.
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Project description:A functional placental barrier is crucial for the supply of the embryo or foetus throughout pregnancy. It is formed by the syncytiotrophoblast, which develops via fusion of cytotrophoblast cells. How this “differentiation-by-fusion” is regulated is only partially understood. Here we analysed transcriptome changes during in vitro cytotrophoblast fusion. Pathway analyses yielded the tumor suppressor p53 as upstream negative regulator and indicated an upregulation of autophagy-related genes. We further showed that, during differentiation, p53 is downregulated on the mRNA and protein levels, while the autophagy marker LC3B-II (lipidated LC3B) is increased. In first-trimester placentae, we find reciprocal expression patterns of p53 and LC3B, with p53 expression primarily in cytotrophoblasts and predominant LC3B expression in the apical side of the syncytiotrophoblast layer. Furthermore, in the syncytiotrophoblast, we could show increased autophagic flux, which is alleviated by ectopically overexpression of p53. This was also shown in placental explants treated with a pharmacological p53 activator. On the contrary, in a fusion-deficient trophoblast cell line we could not see an interdependency of p53 and LC3B lipidation. In summary our data suggests, that the downregulation of p53 during syncytialization is a prerequisite for the activation of autophagy in the placental barrier.
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Project description:Emergency myelopoiesis (EM) is essential in immune defense against pathogens for rapid replenishing of mature myeloid cells. During the EM process, a rapid cell-cycle switch from the quiescent hematopoietic stem cells (HSCs) to highly proliferative myeloid progenitors (MPs) is critical. How the rapid proliferation of MPs during EM is regulated remains poorly understood. Here, we reveal that ATG7, a critical autophagy factor, is essential for the rapid proliferation of MPs during human myelopoiesis. Peripheral blood (PB)-mobilized hematopoietic stem/progenitor cells (HSPCs) with ATG7 knockdown or HSPCs derived from ATG7-/- human embryonic stem cells (hESCs) exhibit severe defect in proliferation during fate transition from HSPCs to MPs. Mechanistically, we show that ATG7 deficiency reduces p53 localization in lysosome for a potential autophagy-mediated degradation. Together, we reveal a previously unrecognized role of autophagy to regulate p53 for a rapid proliferation of MPs in human myelopoiesis.
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Project description:A growing number of studies have shown that p53 modulates metabolic pathways to support diverse biological functions. Given that p53 is most widely known to act as a transcriptional activator, this raises the possibility that p53 transcriptional activity governs metabolic reprogramming. Here, we performed targeted metabolomics and lipidomic analysis which revealed an increase in the de novo biosynthesis of phosphatidylethanolamine (PE) upon p53 activation. Elevated levels of phosphoethanolamine (PEtn), the PE headgroup, in p53 active cells are sustained through PE headgroup recycling, which is partially mediated through the transcriptional activation of autophagy by p53. Disruption of phospholipid headgroup recycling through genetic perturbation of the CDP-ethanolamine pathway results in defects in cell-state specific perturbations in growth and gene expression. Notably, we observe restructuring of endoplasmic reticulum (ER)-mitochondria contacts in cells where headgroup recycling was abrogated, likely an attempt to maintain lipid homeostasis, and this reorganization is reversed when flux through the CDP-Etn pathway is restored. Together, these results suggest that lipid recycling to be an additional tool in the p53 arsenal supporting cellular fitness.
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Project description:A growing number of studies have shown that p53 modulates metabolic pathways to support diverse biological functions. Given that p53 is most widely known to act as a transcriptional activator, this raises the possibility that p53 transcriptional activity governs metabolic reprogramming. Here, we performed targeted metabolomics and lipidomic analysis which revealed an increase in the de novo biosynthesis of phosphatidylethanolamine (PE) upon p53 activation. Elevated levels of phosphoethanolamine (PEtn), the PE headgroup, in p53 active cells are sustained through PE headgroup recycling, which is partially mediated through the transcriptional activation of autophagy by p53. Disruption of phospholipid headgroup recycling through genetic perturbation of the CDP-ethanolamine pathway results in defects in cell-state specific perturbations in growth and gene expression. Notably, we observe restructuring of endoplasmic reticulum (ER)-mitochondria contacts in cells where headgroup recycling was abrogated, likely an attempt to maintain lipid homeostasis, and this reorganization is reversed when flux through the CDP-Etn pathway is restored. Together, these results suggest that lipid recycling to be an additional tool in the p53 arsenal supporting cellular fitness.
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Project description:During tumor growth-when nutrient and anabolic demands are high-autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras-driven tumors additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well-characterized malignant tumor model in Drosophila melanogaster. Micro-computed X-ray tomography and metabolic profiling reveal that Ras<sup>V12</sup> ; scrib<sup>-/-</sup> tumors grow 10-fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, -motility, -feeding, and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. We conclude that host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth.
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