The β-TrCP-Mediated Pathway Cooperates with the Keap1-Mediated Pathway in Nrf2 Degradation In Vivo

Abstract

Nrf2 activates cytoprotective gene expression, and Nrf2 activity is regulated through at least two protein degradation pathways: the Keap1-mediated and β-TrCP-mediated pathways. To address the relative contributions of these pathways, we generated knock-in mouse lines expressing an Nrf2 SA mutant that harbored two substitution mutations of serine residues interacting with β-TrCP.

Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitors

“…Interestingly, some of the reported inhibitors have been observed to preferentially interfere with the DLGex–Keap1 binding compared with the ETGE–Keap1 binding . Considering that the main difference between the Keap1–Nrf2 ETGE interaction and the Keap1–Nrf2 DLGex interaction lies in the P6 subpocket, highlighting the P6 subpocket in drug design might hold enormous promise for the development of Keap1–Nrf2 inhibitors with better selectivity. , In addition, targeting the β-TrCP–Nrf2 pathway has been considered as an unexplored alternative to develop Nrf2 activators with higher target selectivity. ,, Recently, the first β-TrCP - Nrf2 PPI inhibitor has been successfully discovered, which represents a new direction for the future exploitation of safe and potent Nrf2 activators . Mounting evidence suggests that pharmacologic inhibition of BTB and CNC homology 1 (Bach1), a physiological repressor of Nrf2, also represents a promising approach to activate the Nrf2–ARE pathway without involving the electrophilic modification of cellular proteins. , In this regard, BACH1 inhibitors have opened the door for a new class of nonelectrophilic Nrf2 activators. , It is noteworthy that glycogen synthase kinase-3β (GSK-3β) can phosphorylate Nrf2, stimulating its association with β-TrCP and precipitating Nrf2 ubiquitination. , Therefore, GSK-3β inhibitors offer additional ways to activate Nrf2 without electrophilicity concerns. − More attention should be devoted to these areas.…”

“…52,76 In addition, targeting the β-TrCP−Nrf2 pathway has been considered as an unexplored alternative to develop Nrf2 activators with higher target selectivity. 39,143,144 Recently, the first β-TrCP-Nrf2 PPI inhibitor has been successfully discovered, which represents a new direction for the future exploitation of safe and potent Nrf2 activators. 145 Mounting evidence suggests that pharmacologic inhibition of BTB and CNC homology 1 (Bach1), a physiological repressor of Nrf2, also represents a promising approach to activate the Nrf2−ARE pathway without involving the electrophilic modification of cellular proteins.…”

Molecular Basis of the KEAP1-NRF2 Signaling Pathway

“…NRF2 activators targeting the cysteine thiols of KEAP1 have been extensively developed as discussed above and NRF2 activators targeting the KEAP1-NRF2 PPI are also entering the stage of extensive development. It is interesting to note that Cuadrado (2015) has been developing β-transduction repeat-containing protein (β-TRCP)-NRF2 PPI inhibitor in patent (WO2022152800) as [β-TRCP-S-phase kinase-associated protein 1-CULLIN1 (β-TRCP-SKP1-CUL1) E3 ligase complex is also responsible for ubiquitination of NRF2 ( Cuadrado, 2015 ; Kuga et al, 2022 ). Novel NRF2 activators targeting other sites will also be developed.…”

Role of nuclear factor erythroid 2-related factor 2 (Nrf2) in female and male fertility

“…The DSGIS motif in Neh6 helps to recognize the Nrf2 via β-TrCP. The phosphorylation of two serine residues within the DSGIS is crucial for Nrf2 reorganization via β-TrCP [ 31 ]. The Nrf2 activity is suppressed by interaction of the Neh7 domain with the retinoic X receptor alpha (RXRa) [ 32 ].…”