PUBLICATION

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

Authors
Ong, A.J.S., Bladen, C.E., Tigani, T.A., Karamalakis, A.P., Evason, K.J., Brown, K.K., Cox, A.G.
ID
ZDB-PUB-230523-41
Date
2023
Source
Proceedings of the National Academy of Sciences of the United States of America   120: e2217425120e2217425120 (Journal)
Registered Authors
Cox, Andrew, Karamalakis, Anthony
Keywords
KEAP1, NRF2, TFEB/TFE3, lysosome, zebrafish
Datasets
GEO:GSE230611, GEO:GSE230610, GEO:GSE230607
MeSH Terms
  • Lysosomes/metabolism
  • Animals
  • Kelch-Like ECH-Associated Protein 1/genetics
  • Kelch-Like ECH-Associated Protein 1/metabolism
  • NF-E2-Related Factor 2*/metabolism
  • Gene Expression Regulation
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors*/metabolism
(all 7)
PubMed
37216554 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
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.
Genes / Markers
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Expression
Phenotype
No data available
Mutations / Transgenics
Human Disease / Model
No data available
Sequence Targeting Reagents
Target Reagent Reagent Type
bach1aCRISPR4-bach1aCRISPR
bach1aCRISPR3-bach1aCRISPR
bach1bCRISPR3-bach1bCRISPR
bach1bCRISPR4-bach1bCRISPR
flcnCRISPR3-flcnCRISPR
flcnCRISPR4-flcnCRISPR
keap1aCRISPR1-keap1aCRISPR
keap1aCRISPR2-keap1aCRISPR
keap1bCRISPR1-keap1bCRISPR
keap1bCRISPR2-keap1bCRISPR
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Fish
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Engineered Foreign Genes
Marker Marker Type Name
EGFPEFGEGFP
mCherryEFGmCherry
mGreenLanternEFGmGreenLantern
mKate2EFGmKate2
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Mapping
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Citation
Ong, A.J.S., Bladen, C.E., Tigani, T.A., Karamalakis, A.P., Evason, K.J., Brown, K.K., Cox, A.G. (2023) The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis. Proceedings of the National Academy of Sciences of the United States of America. 120:e2217425120e2217425120.