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

Centered on the transcription factor NRF2 and its E3 ligase CUL3^KEAP1, the oxidative stress response protects cells from damage by reactive oxygen species (ROS). Increasing ROS inhibits CUL3^KEAP1 to stabilize NRF2 and elicit antioxidant gene expression, while cells recovering from stress rapidly turn over NRF2 again to prevent reductive stress and oxeiptosis-dependent death. How cells reinitiate NRF2 degradation after ROS have been cleared remains poorly understood. Here, we identify the essential E3 ligase TRIP12 as a crucial 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 oxidative stress is being resolved 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.