Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Oxygen-sensitive methylation of ULK1 is required for hypoxia-induced autophagy

ABSTRACT: Hypoxia is a physiological stress that frequently occurs in solid tissues. Autophagy, a ubiquitous degradation/recycling system in eukaryotic cells, renders cells tolerant to multiple stressors. However, the mechanisms underlying autophagy initiation upon hypoxia remains unclear. This study identifies an oxygen-sensitive methylation of ULK1 with an important role in hypoxic stress adaptation by promoting autophagy induction.

ORGANISM(S): Homo Sapiens

SUBMITTER: Rui Liu

PROVIDER: PXD031209 | iProX | Tue Jan 25 00:00:00 GMT 2022

REPOSITORIES: iProX

ACCESS DATA

Json Xml

Publications

Oxygen-sensitive methylation of ULK1 is required for hypoxia-induced autophagy.

Li Jingyi J Zhang Tao T Ren Tao T Liao Xiaoyu X Hao Yilong Y Lim Je Sun JS Lee Jong-Ho JH Li Mi M Shao Jichun J Liu Rui R

Nature communications 20220304 1

Hypoxia is a physiological stress that frequently occurs in solid tissues. Autophagy, a ubiquitous degradation/recycling system in eukaryotic cells, renders cells tolerant to multiple stressors. However, the mechanisms underlying autophagy initiation upon hypoxia remains unclear. Here we show that protein arginine methyltransferase 5 (PRMT5) catalyzes symmetrical dimethylation of the autophagy initiation protein ULK1 at arginine 170 (R170me2s), a modification removed by lysine demethylase 5C (KD ...[more]

PMID: 35246531

Similar Datasets

Autophagy deficient melanocytes display a senescence associated secretory phenotype that includes oxidized lipid mediators

Project description:Autophagy is a recycling program for cells to adapt to metabolic needs and to stress. Defects in autophagy can affect metabolism, aging, proteostasis and inflammation. We used microarrays to determine the changes in global gene expression in murine melanocyte upon genetic inactivation of the essential autophagy gene Atg7 and as secondary aim wheter the gene regulation by ultraviolet A light is affected by the Atg7 knockout

2019-06-29 | GSE83856 | GEO

Cathepsin L is required for autolysosomal clearance in Drosophila

Project description:Autophagy is a highly conserved lysosomal degrative pathway important for maintaining cellular homeostasis. Much of our current knowledge of autophagy is focused on the initiation steps with the later steps, particularly lysosomal fusion leading to autolysosome formation and the subsequent role of lysosomal enzymes in degradation and recycling become evident. Autophagy can function in both cell survival and cell death, however the mechanisms that distinguish adaptive/survival autophagy from autophagy-dependent cell death remains to be established. Here we use a proteomic analysis of larval midguts during degradation identifying a group of proteins with peptidase activity, suggesting a role in autophagy-dependent cell death. We show that Cathepsin L deficient Drosophila larval midgut cells, accumulate autophagic vesicles due to a block in autophagic flux, yet midgut degradation in not compromised. The accumulation of large aberrant autolysosomes in the absence of Cathepsin function appears to be the consequence of decreased degradative capacity as they contain undigested cytoplasmic material rather and not due to a defect in autophagosome-lysosome fusion. Finally, we find that other Cathepsins are also required for proper autolysosomal degradation in Drosophila larval midgut cells and that this is conserved in mammalian cells. Our findings suggest that Cathepsins play an important degrative role in the autolysosome to maintain autophagy flux, by balancing autophagosome production and turnover (to prevent autophagic stress).

2022-02-15 | PXD016675 | Pride

Systematic analysis of ESCRT mutants reveals an essential function for the MVB pathway in amino acid recycling.

Project description:The ESCRT machinery drives the multivesicular body (MVB) pathway in eukaryotic cells and thus is required for the degradation of ubiquitinated membrane proteins in lysosomes. To systematically characterize how cells respond to loss of ESCRT function, we used quantitative proteomics and gene expression profiling in yeast. We find that ESCRT mutants display severe defects in amino acid homeostasis, resulting in lower levels of free intracellular amino acids. This deficit renders the growth of ESCRT mutants highly sensitive to nutrient limitation. Further proteomic analysis revealed that the MVB pathway essentially contributes to proteome remodeling under nutrient limitation. The rapid decline of protein synthesis upon starvation no longer enables ESCRT mutants to complete their cell cycle and properly enter a quiescent state, which strongly affects their long-term survival. Thus, the MVB pathway functions to selectively down-regulate integral membrane proteins and, together with autophagy and proteasomal degradation, considerably contributes to amino acid recycling. We used microarrays to identify gene expression changes between delta VPS4 knock out and wild type Saccharomyces cerevisiae strains

2018-01-01 | GSE53774 | GEO

Autophagy regulated by the HIF/REDD1/mTORC1 signaling is progressively increased during erythroid differentiation under hypoxia

Project description:For hematopoietic stem and progenitor cells (HSPCs), hypoxia is a specific microenvironment known as the hypoxic niche. The role of hypoxia in maintaining quiescence, self-renewal and proliferation of HSPCs has been more elaborated. What remains unclear is the regulation of hypoxia on HSPC differentiation, especially on the differentiation of HSPCs into erythrocytes. In this study, we show that hypoxia evidently accelerates erythroid differentiation, and in this process effectively enhances autophagy which rapidly supplies cellular components through degradation of organelles or proteins to meet the needs of cell stress or development. In order to ascertain whether autophagy mediates the erythroid differentiation promoted by hypoxia, we analyze the perturbation of erythroid differentiation after pharmacological and genetic interference with autophagy, and address that autophagy is required for hypoxia-accelerated erythroid differentiation. Transcriptomics reveals HIF-1 and mTORC1 pathways may function as the upstream of autophagy to regulate erythroid differentiation under hypoxia. We further determine that mTORC1 signaling is suppressed by hypoxia to relieve its inhibition of autophagy. In addition, we also discover a new regulatory pattern that with the process of erythroid differentiation, mTORC1 activity gradually decreases and autophagy activity increases concomitantly. Moreover, we provide evidence that HIF-1 target gene REDD1, which inhibits mTORC1 activity, is dramatically upregulated under hypoxia. Silencing REDD1 expression activates mTORC1 signaling and impairs the enhanced autophagy and the accelerated erythroid differentiation under hypoxia. Together, our study reveals that hypoxia is conductive to accelerating erythroid differentiation, in which autophagy induced by the HIF-1/REDD1/mTORC1 pathway plays a pivotal role.

2022-04-04 | GSE199778 | GEO

Three-dimensional tumor cell growth stimulates autophagic flux and recapitulates chemotherapy resistance

Project description:Current preclinical models in tumor biology are limited in their ability to recapitulate relevant (patho-) physiological processes, including autophagy. Three-dimensional (3D) growth cultures have frequently been proposed to overcome the lack of correlation between two-dimensional (2D) monolayer cell cultures and human tumors in preclinical drug testing. Besides 3D growth, it is also advantageous to simulate shear stress, compound flux and removal of metabolites, e.g. via bioreactor systems, through which culture medium is constantly pumped at a flow rate reflecting physiological conditions. Here, we show that both Staticic 3D growth and 3D growth within a bioreactor system modulate key hallmarks of cancer cells, including proliferation and cell death as well as macroautophagy, a recycling pathway often activated by highly proliferative tumors to cope with metabolic stress. The autophagy-related gene expression profiles of 2D- and 3D-grown cells are substantially different, with the 3D-grown cells exhibiting an expression profile closely resembling the (patho-) physiological Statice of a tumor. Underscoring the importance of this pathway, autophagy-controlling transcription factors, such as TFEB and FOXO3, are upregulated in tumors, and 3D-grown cells have increased expression compared with cells grown in 2D conditions. Three-dimensional cultures depleted of the autophagy mediators BECN1, ATG5 or ATG7 or the transcription factor FOXO3, are more sensitive to cytotoxic treatment. Accordingly, combining cytotoxic treatment with compounds affecting late autophagic flux, such as chloroquine, renders the 3D-grown cells more susceptible to therapy and increases intracellular doxorubicin concentration to the level of 2D-grown cells. Altogether, 3D cultures are a valuable tool to study drug response of tumor cells, as these models recapitulate (patho-) physiologically relevant pathways, such as autophagy.

2017-07-04 | GSE100020 | GEO

Oxygen-Sensitive Remodeling of Central Carbon Metabolism by Archaic eIF5B

Project description:The eukaryotic translation initiation factor 5B (eIF5B) is a homolog of the ancient IF2, a translation factor that facilitates initiator methionine-tRNAiMet (met-tRNAiMet) delivery to ribosomes in prokaryotes. IF2 evolved during early anaerobic cellular life and can be traced back to the last universal common ancestor. Here, we show that eIF5B is essential for eukaryotic hypoxia tolerance, reminiscent of how IF2 supports prokaryotic anaerobiosis. Global protein synthesis analyses identified eIF5B as a hypoxia-specific translation factor involved in translocating met-tRNAiMet to initiating ribosomes. Systemic translatome studies revealed that eIF5B-dependent mRNAs encode proteins of central carbon metabolism, fructolysis, and other pathways enhanced in organisms inhabiting hypoxic niches. These pathways rely preferentially on eIF5B rather than eIF2, the canonical initiation factor that delivers met-tRNAiMet during aerobic eukaryotic protein synthesis. We suggest that eIF5B/IF2 was retained during evolution of the aerobic eukaryotic lineage to cope with episodes of oxygen deprivation.

2018-01-03 | PXD006799 | Pride

Autophagy is essential for tumor development and survival in hypoxia and in vivo in glioblastoma. (Provisional)

Project description:Hypoxia is negatively associated with glioblastoma patient survival and contributes strongly to tumor resistance. Unfortunately novel anti-angiogenic therapy increases hypoxia and activates survival pathways in tumor cells leading to inevitable tumor relapse. Here we demonstrate that primary glioma cultures and cell lines depend on autophagy to survive severe hypoxia but also at normal oxygen levels. Positive regulators of autophagy are expressed at higher levels in tumor cells and induction in severe hypoxia is more prominent compared to normal brain cells. We demonstrate that autophagy is an essential/critical target for novel treatment in glioblastoma. We show ATG9A is induced by severe hypoxia and could be a novel player of the autophagic response in glioma cells. ATG9A targeting inhibited tumor growth, suggesting an essential role in glioma cell survival in vivo. While autophagy induction was also observed in normal astrocytes, glioma cells displayed a higher sensitivity towards autophagy inhibitors. Importantly, patient-derived cultures exhibited varying sensitivity towards anti-autophagy treatment, where certain cultures were dependent on autophagy already in normoxic conditions. The treatment of tumor bearing mice with the autophagy inhibitor chloroquine significantly increased mice survival, but combination treatment of the agent with bevacizumab did not reveal additive or synergistic effect. The present study demonstrates that inhibition of autophagy using chloroquine as a single agent provides a novel treatment strategy against glioblastoma. It remains to be seen whether autophagy inhibition will improve current standard of care treatment of newly diagnosed glioblastoma patients and whether more specific inhibitors will lead to stronger therapeutic outcome. (Provisional)

2015-11-10 | E-MTAB-3085 | biostudies-arrayexpress

Senescent root proteome in autophagy mutant under nitrogen deficiency

Project description:Macro-autophagy (hereafter referred to as autophagy) is a universal mechanism in eukaryotic cells that facilitates the degradation of unwanted cell constituents. Autophagy is induced in plant under nitrate limiting conditions and autophagy-defective plants are hypersensitive to starvations. Shotgun proteomic analyses were performed on root extracts from atg5 and atg7 mutants harvested after flowering time, when nitrogen remobilization is induced in the leaves as in the roots. The aim of analysis was to clarify the roles of autophagy in the roots when nitrogen recycling and remobilization are enhanced. Study was performed on both nitrate sufficient and nitrate limiting conditions.

2025-07-09 | PXD065985 |

Transcriptional regulation by Pho23 modulates the frequency of autophagosome formation.

Project description:Autophagy as a conserved degradation and recycling machinery is important in normal development and physiology, and defects in this process are linked to many kinds of disease. Because too much or too little autophagy can be detrimental, the process must be tightly regulated both temporally and in magnitude. The transcriptional induction and repression of the autophagy-related (ATG) genes is one crucial aspect of this regulation, but the transcriptional regulators that modulate autophagy are not well characterized. In this study, we identified Pho23 as a master transcriptional repressor for autophagy, with transcriptome profiling revealing that ATG9 is one of the key target genes. Physiological studies with a PHO23 null mutant, or with strains expressing modulated levels of Atg9, demonstrate a critical role of this protein as a regulator of autophagosome formation frequency; Atg9 protein levels correlate with the number of autophagosomes generated upon autophagy induction, and the level of autophagy activity. WT yeast and pho23 deletion mutants were grown under nutrient rich or nitrogen starvation conditions; gene expression was quantified across these 4 samples.

2014-04-24 | E-GEOD-57031 | biostudies-arrayexpress

PHF20 Activates Autophagy Genes through Enhancer Activation via H3K36me2 Binding Activity [RNA-seq]

Project description:Autophagy is a catabolic pathway that maintains cellular homeostasis under various stress conditions, including nutrient-deprived conditions. To elevate autophagic flux to a sufficient level under stress conditions, transcriptional activation of autophagy genes occurs to replenish autophagy components. Here, using combination of RNA-seq, ATAC-seq and ChIP-seq, we demonstrated found that plant homeodomain finger protein 20 (Phf20PHF20), which is an epigenetic reader possessing methyl binding activity, plays a key role in controlling the expression of autophagy genes. PHF20 activates autophagy genes through enhancer activation via H3K36me2 binding activity as an epigenetic reader and that our findings emphasize the importance of nuclear regulation of autophagy.

2022-06-23 | GSE193392 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data