Stress-sensing mechanisms and the physiological roles of the Keap1-Nrf2 system during cellular stress

Abstract

Transcription factor Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes and suppresses the induction of pro-inflammatory cytokine genes. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of Cullin 3-based E3 ubiquitin ligase. Keap1 regulates the activity of Nrf2 and acts as a sensor for oxidative and electrophilic stresses. In this review, we discuss the molecular mechanisms by which the Keap1-Nrf2 system senses and regulates the cellular response to environmental stresses. In particular, we focus on the multiple stress-sensing mechanisms of Keap1 and novel regulatory functions of Nrf2.

Keywords: Keap1; animal model; anti-inflammation; antioxidant; gene regulation; nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2); stress response.

Figure 1.

Nrf2 is the key regulator in two important cytoprotective pathways, anti-inflammation and anti-oxidation. Nrf2 activates genes involved in detoxification (Nqo1 and Gsts), anti-oxidation (Gpx and Txnrd1), and metabolism (G6pd and Gbe1). Conversely, Nrf2 inhibits the induction of pro-inflammatory cytokine gene transcription (IL-6 and IL-1b). Abbreviations used are as follows: Nqo1, NAD(P)H quinone dehydrogenase 1; Gsts, glutathione S-transferases; Gpx2, glutathione peroxidase 2; Txnrd1, thioredoxin reductase 1; G6pd, glucose-6-phosphate dehydrogenase; Gbe1, 1,4-α-glucan branching enzyme 1; IL-6, interleukin-6; and IL-1b, interleukin-1β.

Figure 2.

Molecular dynamics of the Nrf2–Keap1–Cul3 complex in cells. A, two-site binding model of the Nrf2 Neh2 domain and Keap1 homodimer. Note that the ETGE and DLG motifs in the Neh2 domain are high-affinity and low-affinity motifs, respectively. B, in the basal state, a portion of the ubiquitin (Ub) ligase Keap1–Cul3 complex acts as a floodgate and degrades Nrf2 in the proteasome system. In response to oxidative and electrophilic stimuli, Nrf2 accumulates significantly in the nucleus. These stimuli do not affect the abundance and subcellular localization of Keap1 and Cul3 or the interaction of Keap1 with Cul3 and Nrf2. Pooled Nrf2 dimerizes with one of the small Maf proteins (sMaf) to form an Nrf2–sMaf heterodimer that recognizes the ARE and activates target gene expression.

Figure 3.

Model of the multiple stress-sensing mechanisms acting through Keap1. There are five classes of Nrf2 inducers: Class I, Cys-151-preferring; Class II, Cys-288-preferring; Class III, Cys-151/Cys-273/Cys-288-selective; Class IV, Cys-151/Cys-273/Cys-288-independent; and Class V, non-electrophilic. Chemicals representative of each class are shown. Abbreviations used are as follows: tBHQ, tert-butylhydroquinone; DEM, diethyl maleate; DMF, dimethyl fumarate; SFN, sulforaphane; NO, nitric oxide; CDDO, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]; CDDO-Im, CDDO-imidazole; OA-NO2, nitrooctadec-9-enoic acid; 4-HNE, 4-hydroxynonenal; 15d-PGJ2, 15-deoxy-Δ^12,14-prostaglandin J₂; H₂O₂, hydrogen peroxide; PGA2, prostaglandin A2; Dex-Mes, dexamethasone 21-mesylate.