Fig. 1

IKK-CYLD-NRF2 interaction. (A): In the resting cell, a low NRF2 level is present due to the canonical KEAP1-NRF2 interaction and degradation. (B): Various stimuli that activate the IKK signaling pathway also cause mTORC1 activation and autophagy inhibition. mTORC1 reduces NRF2 degradation by phosphorylating p62 scaffold protein, enhancing the p62-KEAP-1 interaction. However, during the terminal phase of signaling, IKK-mediated phosphorylation-dependent deconjugating activity of CYLD inhibits mTORC1, while stimulating the autophagic pathway. Thus, the resultant mTORC1 inhibition and a decrease in p62 level due to the autophagic degradation results in the loss of the p62-KEAP1 relationship. The liberated KEAP1 degrades NRF2 and inhibits its transcription activity