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 functions are associated with cancers and neurodegenerative diseases in humans. However, the function of Nrf2-Keap1 pathway in the developing nervous systems has not been established. Here, we demonstrate a cell-autonomous role of Nrf2-Keap1 pathway, composed of CncC/Nrf2, Keap1 and MafS, in governing neuronal remodeling during Drosophila metamorphosis. Nrf2-Keap1 pathway is activated downstream of the steroid hormone ecdysone signaling. Mechanistically, Nrf2-Keap1 pathway is activated via the cytoplasmic-to-nuclear translocation of CncC in an importin- and ecdysone signaling-dependent manner. Moreover, Nrf2-Keap1 pathway regulates dendrite pruning independently of its canonical antioxidant response pathway, instead, through proteasomal degradation pathway. Thus, this study reveals an epistatic link between Nrf2-Keap1 pathway and steroid hormone signaling, and further demonstrates an antioxidant-independent but proteasome-dependent role of Nrf2-Keap1 pathway in neuronal remodeling.