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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Danio rerio Homo sapiens

PROVIDER: GSE230611 | GEO | 2023/04/30

REPOSITORIES: GEO

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

Project description:The maintenance of redox and metabolic homeostasis is integral to embryonic development. Nuclear factor erythroid 2-related factor 2 (NRF2) is a stress-induced transcription factor that plays a central role in the regulation of redox balance and cellular metabolism. Under homeostatic conditions, NRF2 is repressed by Kelch-like ECH-associated protein 1 (KEAP1). Here, we demonstrate that Keap1 deficiency induces Nrf2 activation and postdevelopmental lethality. 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. These studies identify a role for the KEAP1-NRF2 pathway in the regulation of lysosomal biogenesis and suggest that maintenance of lysosomal homeostasis is required during embryonic development.

| S-EPMC10235939 | biostudies-literature

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

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