Conservation of the Keap1-Nrf2 System: An Evolutionary Journey through Stressful Space and Time

Abstract

The Keap1-Nrf2 system is an evolutionarily conserved defense mechanism against oxidative and xenobiotic stress. Its regulatory mechanisms, e.g., stress-sensing mechanism, proteasome-based regulation of Nrf2 activity and selection of target genes, have been elucidated mainly in mammals. In addition, emerging model animals, such as zebrafish, fruit fly and Caenorhabditis elegans, have been shown to have similar anti-stress systems to mammals, suggesting that analogous defense systems are widely conserved throughout the animal kingdom. Experimental evidence in lower animals provides important information beyond mere laboratory-confined utility, such as regarding how these systems transformed during evolution, which may help characterize the mammalian system in greater detail. Recent advances in genome projects of both model and non-model animals have provided a great deal of useful information toward this end. We herein review the research on Keap1-Nrf2 and its analogous systems in both mammals and lower model animals. In addition, by comparing the amino acid sequences of Nrf2 and Keap1 proteins from various species, we can deduce the evolutionary history of the anti-stress system. This combinatorial approach using both experimental and genetic data will suggest perspectives of approach for researchers studying the stress response.

Identification of compounds that inhibit the binding of Keap1a/Keap1b Kelch DGR domain with Nrf2 ETGE/DLG motifs in zebrafish

“…An interesting observation made in the tree was that all fish carried both Keap1a and Keap1b in them implying that fish regulate Nrf2 by both these co‐ortholog Keap1 proteins. The co‐orthologues appeared during the emergence of vertebrates and lost during the appearance of amniotes . The synteny was exhibited between zebrafish Keap1b and human Keap1.…”

“…The co-orthologues appeared during the emergence of vertebrates and lost during the appearance of amniotes. 50 The synteny was exhibited between zebrafish Keap1b and human Keap1. The conditions that favour the homo-and heterodimerization of these Keap1a and Keap1b in fish remain elusive.…”

Cyclic Peptides in Neurological Disorders: The Case of Cyclo(His-Pro)

“…The heterodimers recognize the antioxidant response elements (AREs) that are enhancer sequences present in the regulatory regions of Nrf2 target genes, essential for the recruitment of key factors for transcription (Suzuki et al, 2013;Suzuki and Yamamoto, 2015). Nrf2 affects the expression of nearly 500 genes that encode proteins acting as redox balancing factors, detoxifying enzymes, stress response proteins, and metabolic enzymes (Fuse and Kobayashi, 2017;Hahn et al, 2015;Yang et al, 2016), thus Nrf2 can be regarded as master regulators of the oxidative stress response. It follows that CHP, with its ability to activate the Nrf2 system, can conceivably be regarded as an antioxidant compound.…”

Reactive Oxygen Species: Radical Factors in the Evolution of Animal Life

“…As discussed, LUCA already possessed the ability to detoxify the O 2 /H 2 O 2 pathway and all organisms – from the simplest bacteria to complex mammals – adapt to oxidative stress by rapidly increasing their production of antioxidants and repairing enzymes . In mammals, the major defense mechanism against oxidative and xenobiotic stress is the Kelch‐like ECH‐associated protein 1 (Keap1)‐NF‐E2‐related factor 2 (Nrf2) system, which is responsible for the transcription of over 200 cytoprotective genes . Given the importance of this pathway, it is possible that it is preserved and modified from simple progenitors .…”

“…[3] In mammals, the major defense mechanism against oxidative and xenobiotic stress is the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system, which is responsible for the transcription of over 200 cytoprotective genes. [93] Given the importance of this pathway, it is possible that it is preserved and modified from simple progenitors. [94] Indeed, recent data analyzing Nrf2 sequences yielded a molecular clock suggesting that Nrf2 first appeared in fungi around 1.5 billion years ago.…”