The Nrf2-Keap1 pathway is activated by steroid hormone signaling to govern neuronal remodeling

The evolutionarily conserved Nrf2-Keap1 pathway is a key antioxidant response pathway that protects cells/organisms against detrimental effects of oxidative stress. Impaired Nrf2 function is associated with cancer and neurodegenerative diseases in humans. However, the function of the Nrf2-Keap1 pathway in the developing nervous systems has not been established. Here we demonstrate a cell-autonomous role of the Nrf2-Keap1 pathway, composed of CncC/Nrf2, Keap1, and MafS, in governing neuronal remodeling during Drosophila metamorphosis. Nrf2-Keap1 signaling is activated downstream of the steroid hormone ecdysone. Mechanistically, the Nrf2-Keap1 pathway is activated via cytoplasmic-to-nuclear translocation of CncC in an importin- and ecdysone-signaling-dependent manner. Moreover, Nrf2-Keap1 signaling regulates dendrite pruning independent of its canonical antioxidant response pathway, acting instead through proteasomal degradation. This study reveals an epistatic link between the Nrf2-Keap1 pathway and steroid hormone signaling and demonstrates an antioxidant-independent but proteasome-dependent role of the Nrf2Keap1 pathway in neuronal remodeling.

Automated summary

The Nrf2-Keap1 pathway plays a cell-autonomous role in governing neuronal remodeling during Drosophila metamorphosis, activated downstream of the steroid hormone ecdysone. It regulates dendrite pruning through proteasomal degradation, independent of its canonical antioxidant response pathway. This study reveals an epistatic link between the Nrf2-Keap1 pathway and steroid hormone signaling in neuronal remodeling.