Role of nrf2 in oxidative stress and toxicity

Abstract

Organismal life encounters reactive oxidants from internal metabolism and environmental toxicant exposure. Reactive oxygen and nitrogen species cause oxidative stress and are traditionally viewed as being harmful. On the other hand, controlled production of oxidants in normal cells serves useful purposes to regulate signaling pathways. Reactive oxidants are counterbalanced by complex antioxidant defense systems regulated by a web of pathways to ensure that the response to oxidants is adequate for the body's needs. A recurrent theme in oxidant signaling and antioxidant defense is reactive cysteine thiol-based redox signaling. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an emerging regulator of cellular resistance to oxidants. Nrf2 controls the basal and induced expression of an array of antioxidant response element-dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure. This review discusses the impact of Nrf2 on oxidative stress and toxicity and how Nrf2 senses oxidants and regulates antioxidant defense.

Figure 1

Versatile reactive cysteine thiol reactions. (a) Biochemistry of reactive cysteine thiols. Reactive cysteine thiols exist as thiolate anions and are prone to oxidation by reactive oxygen and nitrogen species (ROS, RNS). Formation of SNO, S⁻, and SOH is reversible and serves as an intermediate step for disulfide bond formation or modification by other agents, such as fatty acids, amines, metals, and alkylating agents. Reduction of SO₂H to SOH is catalyzed by sulfiredoxin (Srx), whereas formation of SO₃H is irreversible. (b) Redox sensors. In addition to being an antioxidant, thioredoxin (Trx) acts as a sensor of H₂O₂ to activate ASK1-dependent apoptosis or TXNIP-dependent inflammasome assembly.

Figure 2

Domain structure and activation mechanism. (a) Domain structures of Nrf2, Keap1, and small Mafs F, G, and K. (b) Secondary structure of Neh2. (c) Model for activation of Nrf2. Abbreviations: BTB, bric-a-brac, tramtrack, broad-complex domain; bZip, basic region leucine zipper; CNC, cap ‘n’ collar; Cul3, Cullin 3; DGR, double glycine repeat; IVR, intervening region; Keap1, Kelch-like ECH (erythroid cell-derived protein with CNC homology)-associated protein 1; LR, linker region; Maf, musculoaponeurotic fibrosarcoma protein; Neh, Nrf2-ECH homology; Nrf2, nuclear factor erythroid 2–related factor 2.

Figure 3

Nrf2 and oxidant-stimulated programmatic functions. (a) Autophagy. (b) Inflammasome activation. (c) Endoplasmic reticulum (ER) stress and unfolded protein response (UPR). (d ) Mitochondrial redox signaling. Abbreviations: GPx, glutathione peroxidase; Keap1, Kelch-like ECH-associated protein 1; Maf, musculoaponeurotic fibrosarcoma protein; Nrf2, nuclear factor erythroid 2–related factor 2; PERK, protein kinase RNA-like endoplasmic reticulum kinase; Prx, peroxiredoxin; ROS, reactive oxygen species; Srx, sulfiredoxin; Trx, thioredoxin; TrxR, thioredoxin reductase.