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

Ong, AJS; Bladen, CE; Tigani, TA; Karamalakis, AP; Evason, KJ; Brown, KK; Cox, AG

Author(s): Ong, AJS; Bladen, CE; Tigani, TA; Karamalakis, AP; Evason, KJ; Brown, KK; Cox, AG;
Details: Publication Year 2023-05-30,Volume 120,Issue #22,Page e2217425120
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Publication Type: Research article
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.
Publisher: National Academy of Sciences
Keywords: *Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism; Gene Expression Regulation; Kelch-Like ECH-Associated Protein 1/genetics/metabolism; Lysosomes/metabolism; *NF-E2-Related Factor 2/metabolism; Animals; Keap1; Nrf2; Tfeb/tfe3; lysosome; zebrafish
Department(s): Laboratory Research
PubMed ID: 37216554
Publisher's Version: https://doi.org/10.1073/pnas.2217425120
Open Access at Publisher's Site: https://doi.org/10.1073/pnas.2217425120
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-08-16 07:51:11

Last Modified: 2023-08-16 07:51:59