PTEN facilitates lysosome biogenesis and decreases exosome secretion by directly dephosphorylating TFEB
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ABSTRACT:
PROVIDER: PRJNA893213 | ENA |
REPOSITORIES: ENA
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Project description:To investigate the differentially expressed genes in the PTEN_x005f_x0002_intact CCA cells, compared with the PTEN-deficient CCA cells. group.cooperative function KDM4D/NFIB/MLL1 complex in the regulation of adipogenic differentiation, we established
2023-10-20 | GSE216358 | GEO
Project description:Transcription factro-EB (TFEB) is a master gene for autophagy and lysosome biogenesis We used microarrays to detail the gene expression in TFEB-overexpressing endothelial cells and identified distinct classes of TFEB-regulated genes.
2018-05-01 | GSE108384 | GEO
Project description:Transcription factro-EB (TFEB) is a master gene for autophagy and lysosome biogenesis We used microarrays to detail the gene expression in TFEB-overexpressing vascular smooth muscle cells identified distinct classes of TFEB-regulated genes.
2020-11-21 | GSE138000 | GEO
Project description:TFEB has been recently reported to be a key molecule for lysosomal regulation. Renal cell carcinoma (RCC) with t(6;11) (p21;q12) is known to be the only tumor in which TFEB is upregulated. Transcriptome analysis using a whole-genome expression array and pathway analysis using upregulated genes in tumor tissue revealed that the lysosome-associated pathways were significantly deregulated. Total RNA was extracted from non-tumor and tumor in patient of renal cell carcinoma with t(6;11) (p21;q12) and subjected to gene expression microarray analysis.
2013-08-16 | E-GEOD-49901 | 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: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:Mycobacterium tuberculosis (Mtb) infects multiple lung myeloid cell subsets and persists despite innate and adaptive immune responses. However, the mechanisms allowing Mtb to evade elimination by these subsets are not fully understood. Here, we determined that four weeks post infection, after development of adaptive immune responses, CD11clo monocyte-derived lung cells termed MNC1 (mononuclear cell subset 1), harbor more live Mtb compared to alveolar macrophages (AM), neutrophils, and less permissive CD11chi MNC2. Bulk RNA-seq analysis for these subsets identified that lysosome biogenesis pathway is underexpressed in MNC1. Functional assays confirmed that Mtb-permissive MNC1 are deficient in lysosome content, lysosomal acidification, and lysosomal activity compared to AM, and have less nuclear TFEB, a master regulator of lysosome biogenesis. Mtb infection does not alter lysosome deficiency in MNC1. Instead, Mtb recruits MNC1 and MNC2 to the lungs for its spread from AM to these subsets, which depend on Mtb ESX-1 secretion system. Furthermore, nilotinib-mediated TFEB activation enhances lysosome function of primary macrophages in vitro, and MNC1 and MNC2 in vivo, improving control of Mtb infection. Our results suggest that Mtb exploits lysosome-poor monocyte-derived lung cells for persistence; targeting lysosome biogenesis may be an effective approach to host-directed therapy for tuberculosis, enabling permissive lung cells to restrict and kill Mtb through autophagy and other mechanisms.
2023-02-08 | GSE220147 | GEO
Project description:Lysosomes are at the epicenter of cellular processes critical for inflammasome activation in macrophages, including autophagy and lipid metabolism. Inflammasome activation and IL1-beta secretion are implicated in atherogenesis, ischemic cardiac injury and resultant heart failure; however, little is known about the role of macrophage lysosome function in regulating these processes. We hypothesized that macrophages exhibit lysosome dysfunction in heart failure due to ischemic injury, and that augmentation of macrophage lysosomal biogenesis via macrophage-specific overexpression of transcription factor EB (mf-TFEB) would attenuate ischemic remodeling by modulating macrophage inflammatory responses. In both mice subject to ischemia-reperfusion injury, and human heart tissue from patients with ischemic cardiomyopathy, we find evidence of lysosome insufficiency and autophagic impairment, respectively. Mf-TFEB overexpression significantly attenuated post-IR adverse left ventricular remodeling at 4 weeks without affecting scar size. Mf-TFEB overexpression reduced the relative amounts of pro-inflammatory macrophage populations in the myocardium. RNA sequencing of flow-sorted cardiac macrophages post-IR confirmed that TFEB stimulated a lysosomal transcriptional program in macrophages, and upregulated key targets involved in lysosomal lipid metabolism, which we show are critical for inflammasome suppression. Both TFEB-dependent inflammasome suppression and effects on post-IR remodeling were independent of autophagy. Our findings suggest that TFEB reprograms macrophage lysosomal lipid metabolism to attenuate inflammasome activity and protect against post-ischemic cardiac remodeling and simultaneously shift our understanding of how autophagy and lipid metabolism impact acute inflammation.
2019-11-01 | GSE118463 | GEO
Project description:Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy with critical roles in several cancers. Lysosomal autophagy promotes cancer survival through degradation of toxic molecules and maintenance of adequate nutrient supply. Doxorubicin (DOX) is the standard of care treatment for triple-negative breast cancer (TNBC); however, chemoresistance at lower doses and toxicity at higher doses limit its usefulness. By targeting pathways of survival, DOX can become an effective antitumor agent. In this study, we examined the role of TFEB in TNBC and its relationship with autophagy and DNA damage induced by DOX. In TNBC cells, TFEB was hypo-phosphorylated and localized to the nucleus upon DOX treatment. TFEB knockdown decreased the viability of TNBC cells while increasing caspase-3 dependent apoptosis. Additionally, inhibition of TFEB-phosphatase calcineurin sensitized cells to DOX-induced apoptosis in a TFEB dependent fashion. Regulation of apoptosis by TFEB was not a consequence of altered lysosomal function, as TFEB continued to protect against apoptosis in the presence of lysosomal inhibitors. RNA-Seq analysis of TFEB knockdown MDA-MB-231 cells identified a significant downregulation in cell cycle and homologous recombination while genes involved in interferon-γ and TNFα signaling were upregulated. In consequence, knockdown of TFEB was found to disrupt DNA repair following DOX, as evidenced by persistent γH2A.X detection. Together, these findings describe in TNBC a novel lysosomal independent function for TFEB in responding to DNA damage.
2020-12-22 | GSE139203 | GEO
Project description:TFEB has been recently reported to be a key molecule for lysosomal regulation. Renal cell carcinoma (RCC) with t(6;11) (p21;q12) is known to be the only tumor in which TFEB is upregulated. Transcriptome analysis using a whole-genome expression array and pathway analysis using upregulated genes in tumor tissue revealed that the lysosome-associated pathways were significantly deregulated.
2013-08-16 | GSE49901 | GEO