GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2

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Homo sapiens
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In addition to KEAP1:CUL3-mediated degradation in the cytosol, NFE2L2 appears to also be subject to degradation by a BTRC:CUL1 E3 ligase (reviewed in Cuadrado, 2015; Baird and Yamamoto, 2020; Yamamoto et al, 2018). Degradation by the BTRC:CUL1 pathway is mediated by interaction with the NFE2L2 Neh6 domain, and is stimulated by GSK3B-mediated phosphorylation of the Neh6 DSGIS motif. GSK3B-dependent Neh6 phosphorylation is primed by the phosphorylation of a cluster of adjacent serines by unknown kinase(s) (Salazar et al, 2006; Rada et al, 2011; Rada et L, 2012; Rojo et al, 2012; Chen et al, 2017; reviewed in Baird and Yamamoto, 2020). Inhibitory phosphorylation of GSK3B by activated PI3K/AKT signaling relieves BTRC:CUL1-mediated NFE2L2 degradation and provides a biochemical link between activated PI3K signaling and increased NFE2L2 pathway activity (reviewed in Cuadrado, 2015; Baird and Yamamoto, 2020; Yamamoto et al, 2018).
Literature References
PubMed ID Title Journal Year
29717933 The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis

Motohashi, H, Yamamoto, M, Kensler, TW

Physiol Rev 2018
21245377 SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner

Cuadrado, A, Chowdhry, S, Rojo, AI, Rada, P, Hayes, JD, McMahon, M

Mol Cell Biol 2011
32284348 The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway

Yamamoto, M, Baird, L

Mol Cell Biol 2020
31945188 c-Jun NH2 -Terminal Protein Kinase Phosphorylates the Nrf2-ECH Homology 6 Domain of Nuclear Factor Erythroid 2-Related Factor 2 and Downregulates Cytoprotective Genes in Acetaminophen-Induced Liver Injury in Mice

Wang, P, Liao, Y, Liu, K, Wang, H, Gao, Y, Chen, Y, Yao, J, Zhang, J, Liu, Q, Wang, XJ, Tang, X, Wong, CCL, Hai, Y

Hepatology 2020
22751928 Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP axis

Rada, P, Garcia-Mayoral, MF, Cotte, A, Innamorato, NG, Van Leuven, F, Cuadrado, A, Devijver, H, Rojo, AI, Evrard-Todeschi, N, Hayes, JD, Tobón-Velasco, JC, Jaworski, T, Bertho, G

Mol Cell Biol 2012
16551619 Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2

de Sagarra, RM, Velasco, D, Cuadrado, A, Salazar, M, Rojo, AI

J Biol Chem 2006
25937177 Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/β-TrCP

Cuadrado, A

Free Radic Biol Med 2015
22142471 Signaling pathways activated by the phytochemical nordihydroguaiaretic acid contribute to a Keap1-independent regulation of Nrf2 stability: Role of glycogen synthase kinase-3

Cuadrado, A, Medina-Campos, ON, Pedraza-Chaverri, J, Rojo, AI, Rada, P, Zúñiga-Toalá, A, Espada, S, López-Gazcón, A

Free Radic Biol Med 2012
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