Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease

Abstract

Organisms are continually exposed to exogenous and endogenous sources of reactive oxygen species (ROS) and other oxidants that have both beneficial and deleterious effects on the cell. ROS have important roles in a wide range of physiological processes; however, high ROS levels are associated with oxidative stress and disease progression. Oxidative stress has been implicated in nearly all major human diseases, from neurogenerative diseases and neuropsychiatric disorders to cardiovascular disease, diabetes, and cancer. Antioxidant defence systems have evolved as a means of protection against oxidative stress, with the transcription factor Nrf2 as the key regulator. Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress and has been extensively studied in the disease contexts. This review aims to provide the reader with a general overview of oxidative stress and Nrf2, including basic mechanisms of Nrf2 activation and regulation, and implications in various major human diseases.

Keywords: Nrf2; antioxidant; antioxidant response; oxidative stress.

Figure 1

Sources of exogenous and endogenous ROS. ROS can come from toxic exogenous sources in the environment, or be produced as by-products of normal cell metabolism, inflammation, and immunity. ROS may also function as secondary messengers within cell signalling pathways.

Figure 2

Transcriptional regulation of antioxidant genes by the ARE and Nrf2. Nrf2 heterodimerizes with sMaf proteins and binds to the ARE found within the promoter regions of antioxidant and phase II enzyme genes to activate their transcription.

Figure 3

The Keap1-Nrf2 pathway. Under basal conditions, Keap1 is bound to Nrf2, and Nrf2 is ubiquitinated by the Cul3 E3 ubiquitin ligase for degradation by the proteasome. Upon oxidative stress, sensor cysteines in Keap1 are modified by ROS, leading to Nrf2 stabilization, accumulation, and translocation to the nucleus where Nrf2 heterodimerizes with sMaf and binds to the ARE to activate the transcription of antioxidant genes.

Figure 4

Domain structure of human Nrf2. Nrf2 contains seven conserved Neh domains. The Neh2 domain contains two motifs (²⁹DLG³¹ and ⁷⁹ETGE⁸²) wherein Keap1 binds as a substrate adaptor for the Cul3-mediated ubiquitination and degradation of Nrf2.

Figure 5

Domain structure of human Keap1. Keap1 contains three functional domains and a 3-box motif within the proximal part of the IVR domain. The location of all cysteine (C) residues in Keap1 is shown, and key stress-sensing cysteines are marked with an asterisk (*).

Figure 6

Stress-induced cysteine modification of Keap1. Under oxidative stress conditions, specific stress-sensing cysteine residues in Keap1 are modified, leading to a conformational change in Keap1 that results in Nrf2 stabilization, accumulation, and nuclear translocation for the induction of ARE-containing cytoprotective genes.

Figure 7

Two-site substrate recognition model for Keap1-dependent Nrf2 regulation. (A) A Keap1 homodimer binds to the Neh2 domain of Nrf2 at the DLG and ETGE motifs, allowing for the ubiquitination of Nrf2 by Cul3. (B) Stress-sensing cysteine residue(s) in Keap1 are modified by oxidative stress (ROS) causing a conformational change in Keap1 that impairs Nrf2-binding. Nrf2 is stabilized and no ubiquitination occurs.

Figure 8

The aberrant Keap1-Nrf2 pathway in cancer. Some mutations are associated with Nrf2 hyperactivation, which protects cancer cells from ROS and chemotherapeutic agents by increased antioxidant activity.

Figure 9

Nrf2 protects cancer cells from cancer therapy. Cancer cells hijack the Nrf2 pathway to confer protection against cancer therapies such as chemotherapy and radiation. Cancer cells that survive therapy develop resistance and proliferate, leading to chemoresistance and cancer progression.