Stress-activated cap'n'collar transcription factors in aging and human disease

Abstract

Cap'n'collar (Cnc) transcription factors are conserved in metazoans and have important developmental and homeostatic functions. The vertebrate Nrf1, Nrf2, and Nrf3; the Caenorhabditis elegans SKN-1; and the Drosophila CncC comprise a subgroup of Cnc factors that mediate adaptive responses to cellular stress. The most studied stress-activated Cnc factor is Nrf2, which orchestrates the transcriptional response of cells to oxidative stressors and electrophilic xenobiotics. In rodent models, signaling by Nrf2 defends against oxidative stress and aging-associated disorders, such as neurodegeneration, respiratory diseases, and cancer. In humans, polymorphisms that decrease Nrf2 abundance have been associated with various pathologies of the skin, respiratory system, and digestive tract. In addition to preventing disease in rodents and humans, Cnc factors have life-span-extending and anti-aging functions in invertebrates. However, despite the pro-longevity and antioxidant roles of stress-activated Cnc factors, their activity paradoxically declines in aging model organisms and in humans suffering from progressive respiratory disease or neurodegeneration. We review the roles and regulation of stress-activated Cnc factors across species, present all reported instances in which their activity is paradoxically decreased in aging and disease, and discuss the possibility that the pharmacological restoration of Nrf2 signaling may be useful in the prevention and treatment of age-related diseases.

Fig. 1. A phylogenetic tree of the Cnc and Bach transcription factors

A multiple species alignment was constructed using ClustalW (www.ebi.ac.uk/clustalw) and a phylogenetic tree was generated using the Jalview applet. The tree was based on the largest gap-free block of aligned sequences, which contained the DNA binding domains of the Cnc and Bach factors. Accession numbers were: mouse p45 NFE2, NP_032711.2; mouse Nrf1, NP_032712.2; mouse Nrf2, NP_035032.1; mouse Nrf3, NP_035033.1; mouse Bach1, NP_031546.1; mouse Bach2, NP_001103131.1; Drosophila CncC, NP_732833.1; C.elegans SKN-1, NP_741404.1.

Fig. 2. Regulation of the Keap1-Nrf2 antioxidant response pathway

Signaling through the Keap1-Nrf2 antioxidant response pathway is shown in a simplified manner. In basal conditions, Nrf2 is targeted by Keap1 for Cullin3-mediated polyubiquitination and proteasomal degradation. Phase 2 genes are mostly inactive and Antioxidant Response Elements (AREs) in their enhancers are largely bound by small Maf dimers or other repressive factors like Bach1. Oxidants, electrophiles, cancer chemopreventive agents, and other “inducers” impair Nrf2 degradation and facilitate the nuclear accumulation of Nrf2. The activation of Nrf2 is further promoted by positive pathway modulators like DJ-1, p62, and prohibitin. As a result, antioxidant response genes are transcriptionally induced in a coordinated manner through Nrf2-small Maf dimers bound to their AREs, the redox balance is restored, and oxidative damage is minimized. Chronic oxidative stress associated with aging or degenerative diseases handicaps the expression or function (↓) of critical Nrf2 pathway modulators, or increases the abundance (↑) of negative regulators like Keap1 and Bach1. Nrf2 proteolysis is increased, while several other steps (*) of the pathway are reduced. As a result, Nrf2 activity is compromised despite the presence of oxidative conditions. Nrf2-stimulating compounds, like sulforaphane and lipoic acid, induce Nrf2 activity and restore the Cnc antioxidant response.

Fig. 3. Two models for the Keap1-Nrf2 interaction

The molecules are not drawn to scale. (A) Keap1 molecules form dimers through their BTB domains. The “hinge and latch” model proposes that a Keap1 dimer binds a single Nrf2 molecule through high and low affinity interactions with the Neh2 domain’s ETGE (“hinge”) and DLG (“latch”) motifs, respectively. In addition to Nrf2, the Keap1 Kelch domain binds actin, thus tethering the Keap1-Nrf2 complex to the cytoskeleton. Oxidative stress impairs Nrf2 ubiquitination and proteasomal degradation by abolishing only the low affinity “latch” interaction. (B) The “quaternary complex” model proposes that a Keap1 dimer binds two molecules of substrate(s) through high affinity interactions with E(S/T)GE motifs. A Keap1 dimer can bind one Nrf2 molecule and one PGAM5 molecule as shown here, or two Nrf2 molecules (not shown). PGAM5 possesses an N-terminal membrane targeting signal (M), through which the Nrf2-Keap1-PGAM complex is tethered to the cytosolic surface of the outer mitochondrial membrane. Oxidative stress impairs Nrf2 degradation without abolishing the high affinity interaction.