Fig. 1: Mechanistic overview of NRF2 regulation.
From: NRF2 immunobiology in cancer: implications for immunotherapy and therapeutic targeting
A Post-translational control dominates NRF2 regulation across tissue types [1]. The NFE2L2/NRF2 gene is constitutively transcribed and translated [2]. Subsequent to its translation, homodimeric KEAP1 binds the NRF2 protein with high affinity [3, 4]. Given the low binding affinity between KEAP1 and CUL3, it likely that two CUL3 proteins bind KEAP1 after KEAP1:NRF2 co-complex, resulting in NRF2 ubiquitylation [5, 6]. Ubiquitylated NRF2 is then released to the proteasome for degradation simultaneous with release of CUL3 from KEAP1 via the CAND1/2-neddylation cycle. Ultimately, in normal cells not experiencing stress, the rate of this ubiquitylation cycle is envisioned to match the rate of NRF2 production resulting in undetectable levels of NRF2 protein. It is clear that some electrophiles slow the NRF2 degradation cycle by decreasing the KEAP1:CUL3 interaction. B Genomic mechanisms of NRF2 activation in cancer include NRF2 hotspot mutations, KEAP1 inactivating mutations, CUL3 inactivating mutations, and NRF2 copy number amplifications. C Non-genomic mechanisms also activate NRF2 in cancer, including KEAP1 cysteine modifications by fumarate and competitive displacement of NRF2 from KEAP1 through the binding of proteins with an ETGE or ETGE-like motif.
