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

• DOI: 10.1073/pnas.2217425120
• Publication Date: 2023-05-22T19:02:10Z
• Authors: Athena Jessica S....; Cerys E. Bladen; Tara A. Tigani; Anthony P. Karama...; Kimberley J. Evason; Kristin K. Brown; Andrew G. Cox
• Keywords: TFEB; KEAP1; Homeostasis

The maintenance of redox and metabolic homeostasis is integral to embryonic development. Nuclear factor erythroid 2-related 2 (NRF2) a stress-induced transcription that plays central role in the regulation balance cellular metabolism. Under homeostatic conditions, NRF2 repressed by Kelch-like ECH-associated protein 1 (KEAP1). Here, we demonstrate Keap1 deficiency induces Nrf2 activation postdevelopmental lethality. Loss viability preceded severe liver abnormalities characterized an accumulation lysosomes. Mechanistically, loss promotes aberrant EB (TFEB)/transcription binding IGHM Enhancer 3 (TFE3)-dependent lysosomal biogenesis. Importantly, find NRF2-dependent biogenesis cell autonomous evolutionarily conserved. These studies identify for KEAP1–NRF2 pathway suggest required during