Age-related TFEB Downregulation in Proximal Tubules Causes Systemic Metabolic Disorders with Occasional ApolipoproteinA4-related Amyloidosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE270205 | GEO | 2024/12/19
REPOSITORIES: GEO
Similar Datasets
Project description:Age-related TFEB Downregulation in Proximal Tubules Causes Systemic Metabolic Disorders with Occasional ApolipoproteinA4-related Amyloidosis
| PRJNA1125410 | ENA
Project description:We isolated glomeruli with amyloid deposits by performing laser-capture microdissection from formalin-fixed paraffin-embedded samples and identified amyloidosis-related protein using liquid chromatography–tandem mass spectrometry (LC-MS/MS)–based proteomics
2024-12-20 | PXD055311 | JPOST Repository
Project description:The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy. We identify a distinct nuclear interactome of TFEB, with USP7 emerging as a key post-translational modulator of TFEB. Genetic depletion and inhibition of USP7 reveal its critical role in preserving TFEB stability within both nuclear and cytoplasmic compartments. Specifically, USP7 is identified as the deubiquitinase responsible for removing the K48-linked polyubiquitination signal from TFEB at lysine residues K116, K264, and K274, thereby preventing its proteasomal degradation. Functional assays demonstrate the involvement of USP7 in preserving TFEB-mediated transcriptional responses to nutrient deprivation, while also modulating autophagy flux and lysosome biogenesis. As USP7 is a deubiquitinase that protects TFEB from proteasomal degradation, these findings provide the foundation for therapeutic targeting of the USP7-TFEB axis in conditions characterized by TFEB dysregulation and metabolic abnormalities, particularly in certain cancers.
2024-09-17 | PXD055937 | Pride
Project description:Reversible phosphorylation of the transcription factor EB (TFEB) coordinates cellular responses to metabolic and other stresses. During nutrient replete and stressor-free conditions, phosphorylated TFEB is primarily localised to the cytoplasm. Stressor-mediated reduction of TFEB phosphorylation promotes its nuclear translocation and context-dependent transcriptional activity. In this study, we explored targeted dephosphorylation of TFEB as an approach to activate TFEB in the absence of nutrient deprivation or other cellular stress. Through an induction of proximity between TFEB and several phosphatases using the AdPhosphatase system, we demonstrate targeted dephosphorylation of TFEB in cells. Furthermore, by developing a heterobifunctional molecule BDPIC (bromoTAG-dTAG proximity-inducing chimera), we demonstrate targeted dephosphorylation of TFEB-dTAG through induced proximity to bromoTAG-PPP2CA. Targeted dephosphorylation of TFEB-dTAG by bromoTAG-PPP2CA with BDPIC at the endogenous levels is sufficient to induce nuclear translocation and some transcriptional activity of TFEB.
2024-08-09 | PXD053308 | Pride
Project description:Reversible phosphorylation of the transcription factor EB (TFEB) coordinates cellular responses to metabolic and other stresses. During nutrient replete and stressor-free conditions, phosphorylated TFEB is primarily localised to the cytoplasm. Stressor-mediated reduction of TFEB phosphorylation promotes its nuclear translocation and context-dependent transcriptional activity. In this study, we explored targeted dephosphorylation of TFEB as an approach to activate TFEB in the absence of nutrient deprivation or other cellular stress. Through an induction of proximity between TFEB and several phosphatases using the AdPhosphatase system, we demonstrate targeted dephosphorylation of TFEB in cells. Furthermore, by developing a heterobifunctional molecule BDPIC (bromoTAG-dTAG proximity-inducing chimera), we demonstrate targeted dephosphorylation of TFEB-dTAG through induced proximity to bromoTAG-PPP2CA. Targeted dephosphorylation of TFEB-dTAG by bromoTAG-PPP2CA with BDPIC at the endogenous levels is sufficient to induce nuclear translocation and some transcriptional activity of TFEB.
2024-08-09 | PXD053311 | Pride
Project description:Faithful execution of developmental programs relies on the acquisition of unique cell identities from pluripotent progenitors, a process governed by combinatorial inputs from numerous signaling cascades that ultimately dictate lineage-specific transcriptional outputs. Despite growing evidence that metabolism is integrated with many molecular networks, how pathways that control energy homeostasis may affect cell fate decisions is largely unknown. Here, we show that AMPK, a central metabolic regulator, plays critical roles in lineage specification. Although AMPK-deficient embryonic stem cells (ESCs) were normal in the pluripotent state, these cells displayed profound defects upon differentiation, failing to generate chimeric embryos and preferentially adopting an ectodermal fate at the expense of the endoderm during embryoid body (EB) formation. AMPK-/- EBs exhibited reduced levels of Tfeb, a master transcriptional regulator of lysosomes, leading to diminished endolysosomal function. Remarkably, genetic loss of Tfeb also yielded endodermal defects, while AMPK-null ESCs over-expressing this transcription factor normalized their differential potential, revealing an intimate connection between Tfeb/lysosomes and germ layer specification. The compromised endolysosomal system resulting from AMPK or Tfeb inactivation blunted Wnt signaling, while up-regulating this pathway restored expression of endodermal markers. Collectively, these results uncover the AMPK pathway as a novel regulator of cell fate determination during differentiation. 2 WT and 2 AMPK DKO ESC lines were differentiated into embryoid bodies (EBs) for various lengths of time (2, 4, 8, and 12 days) in high and low glucose conditions. Both ESC and EB samples were profiled by mRNA-seq to examine how global gene expression changes associated with ESC differentiation are affected by AMPK deletion.
2016-03-09 | E-GEOD-77705 | biostudies-arrayexpress
Project description:In order to identify the effects of transcription factor EB (TFEB) overexpression on the liver transcriptome, we performed Affymetrix GeneChip hybridization experiments on injected mice overexpressing TFEB specifically in the liver. For the analysis of the injected mice overexpressing TFEB, total RNA was extracted from the liver of three mice. RNA extracted from the liver of 3 not-injected mice was used as a control.
2013-04-20 | E-GEOD-35015 | biostudies-arrayexpress
Project description:Our studies in Salmonella Typhimurium (S. Typhimurium)-infected cells indicate that TFEB has a non-transcriptional, cytosolic function in addition to its well-characterized role as a transcription factor in regulating autophagy and lysosome biogenesis. An unbiased proteomics approach revealed that TFEB interacts with several mitochondrial proteins, which is lost when infected with S. Typhimurium. Microscopical and biochemical examinations further confirmed a novel localization of TFEB in mitochondria. We have also identified a TOMM20 binding motif within the protein sequence of TFEB which, facilitates the mitochondrial translocation in a mTOR-dependent manner. Our results further demonstrate that TFEB and the mitochondrial protease LonP1 co-regulate the assembly of complex I and its function. Moreover, during S. Typhimurium infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines.
2024-05-21 | PXD013758 | Pride
Project description:Total RNA samples from three biological replicates in which TFEB was transiently overexpressed in HeLa cells by transfection using a pcDNA3 vector. As negative control, we used total RNA samples from HeLa cells transfected with an empty pcDNA3 vector. TFEB transfection
2010-04-09 | E-GEOD-16267 | biostudies-arrayexpress
Project description:TFEB, a bHLH-leucine zipper transcription factor belonging to the MiT/TFE family, is a renowned global modulator of cell metabolism by regulating autophagy and lysosomal functions. Remarkably, loss of TFEB in mice causes embryonic lethality due to severe defects in placentation associated with aberrant vascularization and resulting hypoxia. However, the molecular mechanism underlying the described phenotype has yet to be elucidated. By integrating multi-omics approaches with functional assays, we uncover an unprecedented function for TFEB in promoting the formation of a functional syncytiotrophoblast in the placenta. Here, we showed that syncytiotrophoblast formation is marked by TFEB nuclear translocation and its association with the promoters of crucial placental genes, including fusogenic proteins (Syncytin-1 and Syncythin-2) and enzymes involved in the steroidogenic pathway, such as CYP19A1, the rate-limiting enzyme for the synthesis of 17β-Estradiol (E2). Conversely, the depletion of TFEB negatively impacts both the syncytial fusion and the endocrine properties of the syncytiotrophoblast, as demonstrated by a significant decrease in the secretion of placenta hormones and E2 production. Notably, the restoration of TFEB expression resets the syncytiotrophoblast identity. Finally, we identified reduced expression levels of TFEB and its target CYP19A1 in the placenta of pre-eclampsia women, suggesting that dysregulation of the TFEB-CYP19A1 axis might underlie the impairment of placental steroidogenesis described in pre-eclampsia. Our findings elect TFEB as a central controller of the metabolic properties of the placenta by orchestrating both the transcriptional program underlying trophoblast fusion and the acquisition of endocrine function, which are crucial for the bioenergetic requirements of embryonic development.
2024-09-05 | GSE260620 | GEO