Dynamic regulation of the oxidative stress response by the E3 ligase TRIP12

Abstract 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 response 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.