The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation

Abstract

The transcription factor Nrf2 (NF-E2-related factor 2) plays a vital role in maintaining cellular homeostasis, especially upon the exposure of cells to chemical or oxidative stress, through its ability to regulate the basal and inducible expression of a multitude of antioxidant proteins, detoxification enzymes and xenobiotic transporters. In addition, Nrf2 contributes to diverse cellular functions including differentiation, proliferation, inflammation and lipid synthesis and there is an increasing association of aberrant expression and/or function of Nrf2 with pathologies including cancer, neurodegeneration and cardiovascular disease. The activity of Nrf2 is primarily regulated via its interaction with Keap1 (Kelch-like ECH-associated protein 1), which directs the transcription factor for proteasomal degradation. Although it is generally accepted that modification (e.g. chemical adduction, oxidation, nitrosylation or glutathionylation) of one or more critical cysteine residues in Keap1 represents a likely chemico-biological trigger for the activation of Nrf2, unequivocal evidence for such a phenomenon remains elusive. An increasing body of literature has revealed alternative mechanisms of Nrf2 regulation, including phosphorylation of Nrf2 by various protein kinases (PKC, PI3K/Akt, GSK-3β, JNK), interaction with other protein partners (p21, caveolin-1) and epigenetic factors (micro-RNAs -144, -28 and -200a, and promoter methylation). These and other processes are potentially important determinants of Nrf2 activity, and therefore may contribute to the maintenance of cellular homeostasis. Here, we dissect evidence supporting these Keap1-dependent and -independent mechanisms of Nrf2 regulation. Furthermore, we highlight key knowledge gaps in this important field of biology, and suggest how these may be addressed experimentally.

Molecular Targets of Cannabidiol in Neurological Disorders

“…Oxidation of xenobiotics can potentially produce highly reactive intermediates and is why phase I and II metabolism is integrated with electrophilic sensors [e.g., the nuclear factor (erythroid-derived 2)-like 2 (NRF2)-Kelch-like ECH-associated protein 1 pathway), which can upregulate cytoprotective genes and pathways [78]. In this regard, CBD can activate NRF2 [79].…”

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

“…It is the nearest homologue of the kelch protein of Drosophila, which binds to actin (Itoh et al 1999;Zipper and Mulcahy 2002). Keap1 acts as a substrate adapter protein for the E3 ubiquitin ligase complex formed by Cul3 and Rbx1 and targets Nf-E2/Nrf2 for ubiquitination and degradation by the proteasome (McMahon et al 2004;Bryan et al 2013) (Fig. 1).…”

“…Recent reports have shown the importance of the Keap1-Nrf2 system as a therapeutic target for cancer and NDD (Bryan et al 2013). In recent years, both academia and industry have shown immense interest in the Keap1-Nrf2 system targets to discover and develop inhibitors to activate Nrf2 transactivation function by inhibiting the Keap1-Nrf2 interaction.…”

Oxidative and endoplasmic reticulum stress in respiratory disease

“…Thus, ER stress and oxidative stress are intrinsically linked with each process triggering the other in differing scenarios encountered by the cell. Oxidative stress can lead to activation on inflammatory signalling pathways, including via activation of (1) the NFκB transcription factor that regulates inflammatory genes but also can regulate ROS/RNS production and degradation, and (2) the NRF2 transcription factor that primarily regulates the oxidative state of the cell but can also lead to inflammatory signalling 18, 19. Interpretation of studies of ROS/RNS on inflammatory activation pathways is complex as the large number of potential pathways affected by ROS/RNS means that both direct and indirect activation mechanisms occur.…”