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. 2016 Dec;1:80–91. doi: 10.1016/j.cotox.2016.10.002

Figure 1.

Figure 1

Regulation of Nrf2 under homeostatic conditions. Nrf2 is a short-lived protein that is continuously targeted for ubiquitination and proteasomal degradation. Three known ubiquitin ligase systems mediate the degradation of Nrf2: Kelch-like ECH associated protein 1 (Keap1), a substrate adaptor protein for Cullin3 (Cul3)/Rbx1-based Cullin–RING E3 ubiquitin ligase and a cysteine-based sensor for Nrf2 inducers; β-transducin repeat-containing protein (β-TrCP), a substrate adaptor for Skp1–Cullin1 (Cul1)/Rbx1-based Cullin–RING E3 ubiquitin ligase; and the E3 ubiquitin ligase Hrd1 which resides in the endoplasmic reticulum (ER). The relative contributions of these systems towards the degradation of Nrf2 depend on the specific conditions. Degradation mediated by Keap1 requires reduced state of its cysteine sensors. Degradation mediated by β-TrCP requires prior phosphorylation of Nrf2 by glycogen synthase kinase 3 (GSK3). Degradation mediated by Hrd1 occurs during ER stress.