Ingersoll, A. J.; McCloud, D. M.; Hu, J. Y.; Rape, M.

The oxidative stress response is centered on the transcription factor NRF2 and protects cells from reactive oxygen species (ROS). While ROS inhibit the E3 ligase CUL3-KEAP1 to stabilize NRF2 and elicit antioxidant gene expression, cells recovering from stress must rapidly reactivate CUL3-KEAP1 to prevent reductive stress and oxeiptosis-dependent cell death. How cells restore efficient NRF2-degradation upon ROS clearance remains poorly understood. Here, we identify TRIP12, an E3 ligase dysregulated in Clark-Baraitser Syndrome and Parkinson\'s Disease, as a component of the oxidative stress response. TRIP12 is a ubiquitin chain elongation factor that cooperates with CUL3-KEAP1 to ensure robust NRF2 degradation. In this manner, TRIP12 accelerates stress res-ponse silencing as ROS are being cleared, but limits NRF2 activation during stress. The need for dynamic control of NRF2-degradation therefore comes at the cost of diminished stress signaling, suggesting that TRIP12 inhibition could be used to treat degenerative pathologies characterized by ROS accumulation.