Regulation of the oxidative stress response by the E3 ligase TRIP12

Centered on the transcription factor NRF2, the oxidative stress response counteracts reactive oxygen species (ROS) to ensure cell and tissue homeostasis. While unstressed cells constantly degrade NRF2, ROS inhibit the respective E3 ligase, CUL3KEAP1, to stabilize NRF2 and elicit antioxidant gene expression. Following ROS clearance, cells must rapidly reinstate NRF2 degradation, but mechanisms underlying this dynamic regulation are poorly understood. Here, we identify TRIP12, an essential 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 acts after CUL3KEAP1 to extend K29-linked conjugates for efficient NRF2 degradation. TRIP12 accelerates stress response silencing as CUL3KEAP1 is being restored, but limits NRF2 activation during stress. The need for dynamic NRF2 regulation therefore comes at the cost of less responsive stress signaling, suggesting that TRIP12 inhibition could be exploited to bolster the oxidative stress response in neurodegenerative diseases.