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Autophagy driven by a master regulator of hematopoiesis

ABSTRACT: Developmental and homeostatic remodeling of cellular organelles is mediated by a complex process termed autophagy. The cohort of proteins that constitute the autophagy machinery function in a multistep biochemical pathway. Though components of the autophagy machinery are broadly expressed, autophagy can occur in specialized cellular contexts, and mechanisms underlying cell type-specific autophagy are poorly understood. We demonstrate that the master regulator of hematopoiesis GATA-1 directly activates transcription of genes encoding the essential autophagy component Microtubule Associated Protein 1 Light Chain 3B (LC3B) and its homologs (MAP1LC3A, GABARAP, GABARAPL1, GATE-16). In addition, GATA-1 directly activates genes involved in the biogenesis/function of lysosomes, which mediate autophagic protein turnover. We demonstrate that GATA-1 utilizes the forkhead protein FoxO3 to activate select autophagy genes. GATA-1-dependent LC3B induction is tightly coupled to accumulation of the active form of LC3B and autophagosomes, which mediate mitochondrial clearance as a critical step in erythropoiesis. These results illustrate a novel mechanism by which a master regulator of development establishes a genetic network to instigate cell type-specific autophagy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE32491 | GEO | 2011/09/30

SECONDARY ACCESSION(S): PRJNA147759

REPOSITORIES: GEO

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Autophagy driven by a master regulator of hematopoiesis

Project description:Developmental and homeostatic remodeling of cellular organelles is mediated by a complex process termed autophagy. The cohort of proteins that constitute the autophagy machinery function in a multistep biochemical pathway. Though components of the autophagy machinery are broadly expressed, autophagy can occur in specialized cellular contexts, and mechanisms underlying cell type-specific autophagy are poorly understood. We demonstrate that the master regulator of hematopoiesis GATA-1 directly activates transcription of genes encoding the essential autophagy component Microtubule Associated Protein 1 Light Chain 3B (LC3B) and its homologs (MAP1LC3A, GABARAP, GABARAPL1, GATE-16). In addition, GATA-1 directly activates genes involved in the biogenesis/function of lysosomes, which mediate autophagic protein turnover. We demonstrate that GATA-1 utilizes the forkhead protein FoxO3 to activate select autophagy genes. GATA-1-dependent LC3B induction is tightly coupled to accumulation of the active form of LC3B and autophagosomes, which mediate mitochondrial clearance as a critical step in erythropoiesis. These results illustrate a novel mechanism by which a master regulator of development establishes a genetic network to instigate cell type-specific autophagy. Genome-wide maps of GATA1 factor occupancy in primary human PBMC derived erythroblasts

2011-09-30 | E-GEOD-32491 | biostudies-arrayexpress

Identification and characterization of a ribosome receptor for starvation-induced ribophagy

Project description:The lysosome degrades and recycles macromolecules, signals to the master growth regulator mTORC1, and is associated with human disease. Here, we performed quantitative proteomic analyses of lysosomes rapidly isolated using the LysoIP method and find that nutrient levels and mTOR dynamically modulate the lysosomal proteome. We focus on NUFIP1, a protein that upon mTORC1 inhibition redistributes from the nucleus to autophagosomes and lysosomes. Upon these conditions, NUFIP1 interacts with ribosomes and delivers them to autophagosomes by directly binding to LC3B. The starvation-induced degradation of ribosomes via autophagy (ribophagy) depends on the capacity of NUFIP1 to bind LC3B and promotes cell survival. We conclude that NUFIP1 is a receptor for the selective autophagy of ribosomes.

2018-06-21 | PXD009084 | Pride

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

Transcriptional regulation by Pho23 modulates the frequency of autophagosome formation.

2014-04-24 | GSE57031 | GEO

T-cell intracellular antigen (TIA) proteins deficiency in murine embryonic fibroblasts alters cell cycle progression and induces autophagy

Project description:Background: Mice lacking either T-cell intracellular antigen 1 (TIA1) or TIA1-related/like protein (TIAR/TIAL1) show high rates of embryonic lethality, suggesting a relevant role for these proteins during embryonic development. However, intrinsic molecular and cellular consequences of either TIA1 or TIAR deficiency remain poorly defined. Results: By using genome-wide expression profiling approach, we demonstrate that either TIA1 or TIAR inactivation broadly alter normal development-associated signaling pathways in murine embryonic fibroblasts (MEF). Indeed, these analyses highlighted alterations of cytokine-cytokine and ECM-receptor interactions and Wnt, MAPK, TGF-beta dependent signaling pathways. Consistent with these results, TIA1 and TIAR knockout (KO) MEF show reduced rates of cell proliferation, cell cycle progression delay and increased cell size. Furthermore, TIA-proteins deficiency also caused metabolic deficiencies, increased ROS levels and DNA damage, promoting a gentle rise of cell death. Concomitantly, high rates of autophagy were detected in both TIA1 and TIAR KO MEF with induction of the formation of autophagosomes, as evidenced by the up-regulation of the LC3B protein, and autolysosomes, measured by colocalization of LC3B and LAMP1, as a survival mechanism attempt. Conclusions: Taken together, these observations support that TIA proteins orchestrate a transcriptome programme to activate specific developmental decisions. This program is likely to contribute to mouse physiology starting at early stages of the embryonic development. TIA1/TIAR might function as cell sensors to maintain homeostasis and promote adaptation/survival responses to developmental stress. Two independent replicates were performed for each experimental condition and hybridized to Agilent SurePrint G3 Mouse 8x60 microarrays.

2014-11-05 | E-GEOD-43077 | biostudies-arrayexpress

Downregulation of p53 drives autophagy during human trophoblast differentiation

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.

2017-10-10 | GSE98523 | GEO

Hesketh_LC3B_vs_C_P116_Coelho_et_al_2021_08_13

Project description:This paper compares the proximity-interactions between LC3B vs LC3C using BioID. It describes a pathway through which endocytosed cargo is diverted to autophagosomes.

2021-08-13 | MSV000087983 | MassIVE

Role of OSGIN1 in Mediating Smoking-induced Autophagy in the Human Airway Epithelium [array]

Project description:Enhanced autophagy is recognized as a component of the pathogenesis of smoking-induced airway disease. Based on the knowledge that enhanced autophagy is linked to oxidative stress and the DNA damage response, both of which are linked to smoking, we used microarray analysis of the small airway epithelium to identify smoking up-regulated genes known to re-spond to oxidative stress and the DNA damage response. This analysis identified OSGIN1 as significantly up-regulated by smoking in both the large and small airway epithelium (1.8-fold, p<0.01, 2.1-fold, p<10-4, respectively), an observation confirmed by an independent small airway microarray cohort, TaqMan PCR and RNAseq. Genome-wide correlation of RNAseq analysis of airway basal/progenitor cells isolated from healthy subjects (n=17) showed a direct correlation of OSGIN1 mRNA levels to multiple classic autophagy genes, including, LC3B, P62, WIPI1 and ATG13 (all rho>0.7, p<0.01). In vitro cigarette smoke extract exposure of nonsmoker primary airway basal/progenitor cells was accompanied by a dose-dependent up-regulation of OSGIN1 and autophagy induction. Lentivirus-mediated enhanced expression of OSGIN1 in human primary basal/progenitor cells induced puncta-like staining of LC3B and up-regulation of LC3B mRNA and protein and P62 mRNA expression level in a dose and time-dependent manner. OSGIN1-induction of autophagosome / amphistome / autolysosome formation was confirmed by co-localization of LC3B with P62 or CD63 (endosome marker) and LAMP1 (lysosome marker). Induction of autophagy by OSGIN1 is accompanied with heightened oxidative stress. Together, these observations support the concept that smoking-induced up-regulation of OSGIN1 is at least one link between smoking-induced stress and enhanced-autophagy in the human airway epithelium.

2017-08-31 | GSE76324 | GEO

Role of OSGIN1 in Mediating Smoking-induced Autophagy in the Human Airway Epithelium [RNA-Seq]

2017-08-31 | GSE76326 | GEO

T-cell intracellular antigen (TIA) proteins deficiency in murine embryonic fibroblasts alters cell cycle progression and induces autophagy

2014-11-05 | GSE43077 | GEO