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Lysosomal signaling licenses embryonic stem cell differentiation via inactivation of Tfe3

ABSTRACT: Lysosomal signaling licenses embryonic stem cell differentiation via inactivation of Tfe3

PROVIDER: PRJNA422369 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6375660.fastq.gz	Fastqsanger.gz
	SRR6375670.fastq.gz	Fastqsanger.gz
	SRR6375680.fastq.gz	Fastqsanger.gz
	SRR6375690.fastq.gz	Fastqsanger.gz
	SRR6375661.fastq.gz	Fastqsanger.gz

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Lysosomal signaling licenses embryonic stem cell differentiation via inactivation of Tfe3

Project description:Self-renewal and differentiation of pluripotent murine embryonic stem cells (ESCs) is regulated by extrinsic signaling pathways. It is less clear whether cellular metabolism instructs developmental progression. In an unbiased genome-wide CRISPR/Cas9 screen, we identified components of a conserved amino acid-sensing pathway as critical drivers of ESC differentiation. Functional analysis revealed that lysosome activity, the Ragulator protein complex, and the tumor-suppressor protein Folliculin enable the Rag GTPases C and D to bind and seclude the bHLH transcription factor Tfe3 in the cytoplasm. In contrast, ectopic nuclear Tfe3 represses specific developmental and metabolic transcriptional pro- grams that are associated with peri-implantation development. We show differentiation-specific and non-canonical regulation of Rag GTPase in ESCs and, importantly, identify point mutations in a Tfe3 domain required for cytoplasmic inactivation as potentially causal for a human developmental disorder. Our work reveals an instructive and biomedically relevant role of metabolic signaling in licensing embryonic cell fate transitions.

2018-12-18 | GSE108057 | GEO

Transcriptional regulation of the innate immune reponse by the MITF/TFE3 family

Project description:To understand the activation of the MITF/TFE transcription factors in effective defense against pathogens we examined the genome wide distribution of TFE3 in control and activated mouse macrophages. It was determined that TFEB and TFE3 collaborate with each other to promote efficient autophagy induction, increased lysosomal biogenesis, and transcriptional upregulation of proinflammatory cytokines and key mediators of the inflammatory response. 4 samples were analyzed: Background Control, Control, Starvation, LPS

2016-02-01 | E-GEOD-75822 | biostudies-arrayexpress

mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes

Project description:To stimulate cell growth, the protein kinase complex mTORC1 requires intracellular amino acids for activation. Amino-acid sufficiency is relayed to mTORC1 by Rag GTPases on lysosomes, where growth factor signaling enhances mTORC1 activity via the GTPase Rheb. In the absence of amino acids, GATOR1 inactivates the Rags, resulting in lysosomal detachment and inactivation of mTORC1. We demonstrate that in human cells, the release of mTORC1 from lysosomes depends on its kinase activity. In accordance with a negative feedback mechanism, activated mTOR mutants display low lysosome occupancy, causing hypo-phosphorylation and nuclear localization of the lysosomal substrate TFE3. Surprisingly, mTORC1 activated by Rheb does not increase the cytoplasmic/lysosomal ratio of mTORC1, indicating the existence of mTORC1 pools with distinct substrate specificity. Dysregulation of either pool results in aberrant TFE3 activity and may explain nuclear accumulation of TFE3 in epileptogenic malformations in focal cortical dysplasia type II (FCD II) and tuberous sclerosis (TSC).

2024-11-26 | PXD043611 | Pride

The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis [RNA-seq: 7dpf_liver]

Project description:Under homeostatic conditions, NRF2 is repressed by Kelch-like ECH-associated protein 1 (KEAP1). Here, we demonstrate that Keap1 deficiency induces Nrf2 activation and post-developmental lethality in zebrafish larvae. Loss of viability is preceded by severe liver abnormalities characterized by an accumulation of lysosomes. Mechanistically, we demonstrate that loss of Keap1 promotes aberrant activation of transcription factor EB (TFEB)/transcription factor binding to IGHM Enhancer 3 (TFE3)-dependent lysosomal biogenesis. Importantly, we find that NRF2-dependent regulation of lysosomal biogenesis is cell autonomous and evolutionarily conserved.

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The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis [RNA-seq: 7dpf_larvae]

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Tfe3-bound regions in naive pluripotent mouse embryonic stem (ES) cells

Project description:The bHLH transcription factor Tfe3 is a powerful regulator of pluripotency and we report a genome-wide analysis of Tfe3 occupancy in mouse ES cells. Nuclear localization of Tfe3 is inhibited by a protein complex containing the tumor-suppressor Folliculin (Flcn) and we also determine Tfe3 binding sites in ES cells expressing an shRNA targeting Flcn. Specificity is controlled for by using unspecific IgGs and ES cells expressing an shRNA targeting Tfe3. ChIP-Seq profiling of Tfe3 in ES cells

2013-04-10 | E-GEOD-39815 | biostudies-arrayexpress

The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis [RNA-seq: HepG2 cells sitfebtfe3]

2023-04-30 | GSE230609 | GEO

The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis [RNA-seq: HepG2 cells KeapKO]

2023-04-30 | GSE230608 | GEO

ESCRT-I controls lysosomal membrane protein homeostasis and restricts MCOLN1-dependent TFEB/TFE3 signaling.

Project description:Within the endolysosomal pathway in mammalian cells, ESCRT complexes facilitate degradation of membrane proteins from limiting membranes of late endosomes. Recent studies revealed that yeast ESCRT proteins also sort for degradation, ubiquitinated proteins from vacuolar membrane. However, whether mammalian ESCRTs perform similar function at lysosomes remained unknown. Here, we studied the involvement of mammalian ESCRT-I in maintaining lysosomal membrane homeostasis and its implication in lysosome-related signaling. We show that ESCRT-I restricts the size of lysosomes and promotes degradation of lysosomal Ca2+ channel, MCOLN1 protein. ESCRT-I depletion induced transcriptional response related to MiT-TFE signaling and cholesterol biosynthesis, pointing to lysosomal dysfunction. The lack of ESCRT-I promoted abnormal cholesterol accumulation on lysosomes and activated TFEB/TFE3 transcription factors in Ca2+-MCOLN1-dependent, but lipid-independent manner. Hence, our study provides evidence that ESCRT-I maintains lysosomal homeostasis and elucidates MiT-TFE regulatory mechanism activated in response to ESCRT-I deprivation

2022-03-28 | GSE178665 | GEO

The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis

Project description:The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis

| PRJNA961964 | ENA