Keap1 and Nrf2 play important role in cellular proteostasis and are key regulators in corresponding signaling pathways leading, in particular to autophagy. Keap1 is subjected to succination at cystein residues, whereas Nrf2 to ubiquitination.

I think that this short review could help you in better understanding  better Keap1/Nrf2 signaling and providing references to original articles.

E. Kansanen et al. / Redox Biology 1 (2013) 45–49 

Hi Ethan,

it has been known that Keap1 binds Nrf2 in the cytoplasm and promotes its proteasomal degradation. Keap1 consists of reactive cysteines that can be subjected to oxidants or electrophiles exposures. This modification causes allosteric changes in Keap1 conformation that prevent the marking of Nrf2 degradation. Thus, Nrf2 protein that eludes degradation accumulates and after possible post-translational modifications (e.g., phosphorylation), goes inside the nucleus and bind to antioxidant response element (ARE) sequences that occur in the regulatory regions of its target genes.

One of the effects on post-translational modification of Keap1 cysteines by succinylation occurs in familial papillary renal carcinoma due to the loss of fumarate hydratase enzyme activity. This post-translational modification leads to the disruption of Keap1/Nrf2 interaction and nuclear accumulation of Nrf2.

Recent reports have suggested that Nrf2 as a downstream factor of many kinases. However, so far there is no modification reported to occur on Nrf2 that results in dissociation of the Keap1-Nrf2 complex in vivo. It is also possible that post-translational modification may occur on Keap1, leading to dissociation of the Nrf2-Keap1 complex.

I suggest you to look at these reviews:1) Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev. 2006;38(4):769-89; 2) Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL. The Keap1-Nrf2 pathway:Mechanisms of activation and dysregulation in cancer. Redox Biol. 2013 Jan 18;1:45-9.

I hope this will help you.

Best regards,

Federico Pio Fabrizio

Great thank you!