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

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

Journal article

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

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

Proceedings of the National Academy of Sciences of the United States of America | Published : 2023

DOI: 10.1073/pnas.2217425120

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 fa..

View full abstract

University of Melbourne Researchers

Athena Ong Author

Kristin Brown Author

Andrew Cox Author

Related Projects (2)

ADAPTIVE REPROGRAMMING OF METABOLISM IN REGENERATION

. Biologists have long been intrigued at the phenomenon of organ regeneration. Unlike most human organs, the liver exhibits the remarkable c..

Investigating the consequences of dysregulated lipogenesis in cancer

Reprogramming of cellular metabolism is a hallmark of cancer. As such, there has been growing interest in developing strategies to exploit m..

Grants

Awarded by National Institutes of Health

Funding Acknowledgements

& nbsp;A.J.S.O. and T.A.T. are supported by Australian Government Research Training Program Scholarships. K.J.E. is funded by NIH/NCI (R01CA222570) and the Damon Runyon Cancer Research Foundation (Damon Runyon-Rachleff Innovation Award DRR-61-20) . A.G.C. is supported by a National Health and Medical Research Council (NHMRC) Investigator Grant (GNT1176650) , and an Australian Research Council Discovery Project Grant (DP200102693) . K.K.B. is supported by NHMRC Ideas Grants (GNT2004212 and GNT2012313) and a Victorian Cancer Agency Mid-Career Research Fellowship (MCRF17020) . K.K.B and A.G.C. are also jointly supported by the Peter MacCallum Cancer Foundation (Ted and Lila Seehusen Foundation) . We acknowledge support from the Peter MacCallum Cancer Centre Foundation and the Australian Cancer Research Foundation. This research used National Collaborative Research Infrastructure Strategy-enabled Metabolomics Australia infrastructure at the University of Melbourne, funded through BioPlatforms Australia. We extend our thanks to the Peter MacCallum Cancer Centre Core Facilities and their staff who provided support for this work; namely the Centre for Advanced Histology & amp; Microscopy, the Molecular Genomics Core, the Flow Cytometry Core and the Bioinformatics Core Facilities. We also thank the staff involved at the University of Melbourne Zebrafish Core Facility. Finally, we thank members of the Cox Laboratory and Brown Laboratory (Peter MacCallum Cancer Centre) for helpful discussions.