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

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

PROVIDER: PRJNA961971 | ENA |

REPOSITORIES: ENA

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

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.

2023-04-30 | GSE230609 | GEO

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

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

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

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

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

| PRJNA961964 | ENA

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

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

| PRJNA961972 | ENA

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

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

| PRJNA961973 | ENA

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

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

| PRJNA961970 | ENA

TFEB AND TFE3 DRIVE KIDNEY CYSTOGENESIS AND TUMORIGENESIS

Project description:Birt-Hogg-Dubè (BHD) syndrome is an inherited condition caused by loss-of-function mutations in the gene encoding the tumor-suppressor protein folliculin (FLCN) and frequently associated with kidney cysts and cancer. FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We previously showed that deletion of TFEB rescued the renal cystic phenotype of kidney-specific Flcn KO mice. Using Flcn/TFEB/TFE3 double and triple KO mice we now show that both TFEB and TFE3 contribute, in a differential and cooperative manner, to kidney cystogenesis. Importantly, silencing of either TFEB or TFE3 rescued tumorigenesis in patient-derived xenografts (PDXs) generated from a kidney tumor of a BHD patient. Furthermore, transcriptome analyses performed in transgenic mice, PDXs and patient tumor samples revealed TFEB/TFE3 downstream targets that may contribute to their tumorigenic activity. Our findings demonstrate in disease-relevant models that TFEB and TFE3 are key drivers of kidney tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors.

2023-04-04 | PXD035450 | Pride

The FACT complex facilitates expression of lysosomal and antioxidant genes through binding to TFEB and TFE3 [RNA-seq]

Project description:The transcription factors TFEB and TFE3 orchestrate the cellular response to a variety of stressors, including nutrient deprivation, oxidative stress, and pathogens. Here we describe a novel interaction between TFEB/TFE3 and FACT, a heterodimeric histone chaperone consisting of SSRP1 and SPT16 that mediates nucleosome disassembly and assembly, thus facilitating transcription. Extracellular stimuli, such as nutrient deprivation or oxidative stress, induce nuclear translocation and activation of TFEB and TFE3, which then associate with the FACT complex to regulate stress-induced gene transcription. Depletion of FACT does not affect TFEB activation, stability, or binding to the promoter of target genes. In contrast, reduction of FACT levels by siRNA or treatment with the FACT inhibitor curaxin, severely impair induction of numerous antioxidant and lysosomal genes, revealing a crucial role of FACT as a regulator of cellular homeostasis. Furthermore, upregulation of antioxidant genes induced by TFEB over-expression is significantly reduced by curaxin, consistent with a role of FACT as a TFEB transcriptional activator. Together, our data show that chromatin remodeling at the promoter of stress-responsive genes by FACT is important for efficient expression of TFEB/TFE3 targets, thus providing a link between environmental changes, chromatin modifications and transcriptional regulation.

2022-04-21 | GSE180323 | GEO

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