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Review
. 2010 Dec 1;13(11):1699-712.
doi: 10.1089/ars.2010.3211. Epub 2010 Aug 14.

Regulation of the Nrf2-Keap1 antioxidant response by the ubiquitin proteasome system: an insight into cullin-ring ubiquitin ligases

Nicole F Villeneuve  1 , Alexandria Lau, Donna D Zhang
Affiliations
Review

Regulation of the Nrf2-Keap1 antioxidant response by the ubiquitin proteasome system: an insight into cullin-ring ubiquitin ligases

Nicole F Villeneuve et al. Antioxid Redox Signal. .

Abstract

Nrf2 is a transcription factor that has emerged as the cell's main defense mechanism against many harmful environmental toxicants and carcinogens. Nrf2 is negatively regulated by Keap1, a substrate adaptor protein for the Cullin3 (Cul3)-containing E3-ligase complex, which targets Nrf2 for ubiquitination and degradation by the ubiquitin proteasome system (UPS). Recent evidence suggests that constitutive activation of Nrf2, due to mutations in Keap1 or Nrf2, is prominent in many cancer types and contributes to chemoresistance. Regulation of Nrf2 by the Cul3-Keap1-E3 ligase provides strong evidence that tight regulation of Cullin-ring ligases (CRLs) is imperative to maintain cellular homeostasis. There are seven known Cullin proteins that form various CRL complexes. They are regulated by neddylation/deneddylation, ubiquitination/deubiquitination, CAND1-assisted complex assembly/disassembly, and subunit dimerization. In this review, we will discuss the regulation of each CRL using the Cul3-Keap1-E3 ligase complex as the primary focus. The substrates of CRLs are involved in many signaling pathways. Therefore, deregulation of CRLs affects several cellular processes, including cell cycle arrest, DNA repair, cell proliferation, senescence, and death, which may lead to many human diseases, including cancer. This makes CRLs a promising target for novel cancer drug therapies.

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Figures

FIG. 1.
FIG. 1.
A schematic of the Cul3-Keap1-E3 ligase. Cul3 serves as a scaffolding protein that binds the Ub-loaded E2, Rbx1, and Keap1 proteins. Following Nedd8 conjugation (blue circle), a Keap1 homodimer functions as a substrate adaptor to recruit Nrf2 to the Cul3–Keap1–E3 ligase complex for ubiquitination.
FIG. 2.
FIG. 2.
A general schematic of the seven Cullin-ring ligases. (A) Cul1, (B) Cul2, (C) Cul3, (D) Cul4A/B = Cul4A and Cul4B, (E) Cul4B, (F) Cul5, and (G) Cul7 Cullin-ring ligases. Words listed in red are all domain names. BPA, BPB, and BPC are the three propeller domains of DDB1.
FIG. 3.
FIG. 3.
Activation of the NF-κB signaling pathway. Various stimuli can lead to phosphorylation and activation the IKK complex composed of three subunits, IKKα, IKKβ, and IKKγ. Upon activation, IKKβ phosphorylates two serine residues in IκBα that targets it for degradation by the Cul1-β-TrCP1–E3 ligase complex. As a result, the NF-κB complex (p50 and p65) is released, exposing a nuclear localization signal (NLS) that allows the NF-κB complex to translocate to the nucleus and bind to κB sites in the promoters of downstream genes to induce their transcription.
FIG. 4.
FIG. 4.
Regulation of β-catenin by the Cul1–Skp1–E3 ligase complex. In the absence of Wnt signaling, β-catenin forms a complex with GSK3β, casein kinase 1α (CK1α), Axin, and adenomatous polyposis coli (APC), resulting in CK1α-mediated phosphorylation of β-catenin (S45), followed by GSK3β-mediated phosphorylation of β-catenin at additional residues (T41, S37, S33). Phosphorylation of β-catenin allows it to be recognized by βTrCP1 and targeted for ubiquitination by the Cul1–Skp1–E3 ligase and subsequent degradation by the 26S proteasome.
FIG. 5.
FIG. 5.
Regulation of the Cul3–Keap1–E3 ligase complex. The Cul3–Keap1–E3 ligase complex is active when it is in the neddylated state, which facilitates the docking of a Keap1 homodimer-bound to Nrf2 into the complex, resulting in ubiquitination and degradation of Nrf2. The complex is inactivated by deneddylation. The CSN complex removes Nedd8 from Cul3 enhancing the association of Cul3 and CAND1, which triggers dissociation of Keap1-Nrf2 from Cul3. Finally, neddylation can reactivate the E3 ligase complex. The complex can also be reactivated following deneddylation without disassembly of the complex. UBC12 can conjugate Nedd8 back onto Cul3 without dissociation of Keap1 from the Cul3–Rbx1 core complex (red arrow).
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