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TFEB-driven lysosomal biogenesis is pivotal for PGC1a-dependent renal stress resistance

ABSTRACT: TFEB-driven lysosomal biogenesis is pivotal for PGC1a-dependent renal stress resistance

PROVIDER: PRJNA521410 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8548540_1.fastq.gz	Fastqsanger.gz
	SRR8548540_2.fastq.gz	Fastqsanger.gz
	SRR8548550_1.fastq.gz	Fastqsanger.gz
	SRR8548550_2.fastq.gz	Fastqsanger.gz
	SRR8548541_1.fastq.gz	Fastqsanger.gz

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TFEB-driven lysosomal biogenesis is pivotal for PGC1a-dependent renal stress resistance

Project description:Because injured mitochondria can accelerate cell death through the elaboration of oxidative free radicals and other mediators, it is somewhat paradoxical that proliferator gamma coactivator 1-alpha (PGC1a), a stimulator of increased mitochondrial abundance, protects stressed renal cells instead of potentiating injury. Here we report that PGC1a’s induction of lysosomes via transcription factor EB (TFEB) may be pivotal for kidney protection. CRISPR and stable gene transfer showed that PGC1a knockout tubular cells were sensitized to the genotoxic stressor cisplatin whereas transgenic cells were protected. The biosensor mtKeima unexpectedly revealed that cisplatin blunts mitophagy both in cells and mice. PGC1a not only counteracted this effect but also raised basal mitophagy, as did the downstream mediator nicotinamide adenine dinucleotide (NAD+). PGC1a did not consistent affect known autophagy pathways modulated by cisplatin. Instead RNA sequencing identified coordinated regulation of lysosomal biogenesis via TFEB. This effector pathway was sufficiently important that inhibition of TFEB or lysosomes unveiled a striking harmful effect of excess PGC1a in cells and conditional mice. These results uncover an unexpected effect of cisplatin on mitophagy and PGC1a’s exquisite reliance on lysosomes for kidney protection. Finally, the data illuminate TFEB as a novel target for renal tubular stress resistance.

2019-06-10 | GSE126259 | GEO

Mitochondrial energetic stress triggers AMPK/FNIP1-dependent TFEB nuclear translocation, inducing transcriptional waves of lysosomal and mitochondrial biogenesis.

Project description:Cells respond to mitochondrial energetic stress with rapid activation of the AMP-activated protein kinase (AMPK), which acutely inhibits anabolism and stimulates catabolism. AMPK also induces sustained transcriptional reprogramming of metabolism. The TFEB transcription factor is a major effector of AMPK signals, inducing lysosome genes following energetic stress. Yet the molecular mechanism underlying how AMPK activates TFEB remains unresolved. We demonstrate here that AMPK directly phosphorylates five conserved serine residues in FNIP1, which suppresses the function of the FLCN/FNIP1 RagC GAP complex, in turn controlling TFEB lysosomal localization. We demonstrate that FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB, which is fully separable from AMPK control of canonical mTORC1 signaling. Using a non-phosphorylatable allele of FNIP1, we show that in parallel to lysosomal biogenesis, AMPK induces mitochondrial biogenesis via TFEB-dependent induction of PGC1a mRNA. This signaling from mitochondrial stress is also independent of amino-acid control of the Rags and TFEB, which still proceed normally in cells bearing the AMPK-non phosphorylatable allele of FNIP1. Taken together, mitochondrial energetic stress triggers AMPK/FNIP1-dependent TFEB nuclear translocation, inducing transcriptional waves of lysosomal and mitochondrial biogenesis.

2023-05-08 | GSE218827 | GEO

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.

2023-04-30 | GSE230610 | GEO

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 [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

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

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

| PRJNA961964 | ENA

Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection

Project description:Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic and degenerative disease in humans. Here, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B downregulated mTOR activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via the transcription factor TFEB, which increased lysosomal biogenesis and activation of autophagy-initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome population and basic recycling functions in the cell. We used microarrays to explore the gene expression profiles differentially expressed in bone marrow-derived macrophages (BMDM) isolated from cathepsin B-/- and wild-type mice.

2016-08-04 | E-GEOD-79508 | biostudies-arrayexpress

TFEB promotes prostate cancer progression via regulating ABCA2-dependent lysosomal biogenesis

Project description:TFEB promotes prostate cancer progression via regulating ABCA2-dependent lysosomal biogenesis

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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