| RRC ID |
83917
|
| Author |
Ong AJS, Bladen CE, Tigani TA, Karamalakis AP, Evason KJ, Brown KK, Cox AG.
|
| Title |
The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis.
|
| Journal |
Proc Natl Acad Sci U S A
|
| 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.
|
| Volume |
120(22)
|
| Pages |
e2217425120
|
| Published |
2023-5-30
|
| DOI |
10.1073/pnas.2217425120
|
| PMID |
37216554
|
| PMC |
PMC10235939
|
| MeSH |
Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors* / metabolism
Gene Expression Regulation
Kelch-Like ECH-Associated Protein 1 / genetics
Kelch-Like ECH-Associated Protein 1 / metabolism
Lysosomes / metabolism
NF-E2-Related Factor 2* / metabolism
|
| Resource |
| Zebrafish |
Tg(-3.5gstp1:GFP)it416b |
