Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles

Abstract

Electrophile responsive element (EpRE)-mediated gene induction is a pivotal mechanism of cellular defense against the toxicity of electrophiles and reactive oxygen species (ROS). Nrf2, which belongs to the cap'-n'-collar family of basic region-leucine zipper transcription factors, has emerged as an essential component of an EpRE-binding transcriptional complex. Detailed analysis of the regulatory mechanism governing Nrf2 activity led to the identification of Keap1, which represses Nrf2 activity by directly binding to the N-terminal Neh2 domain. Keap1 interaction with Neh2 leads to the sequestration of Nrf2 in the cytoplasm and to the enhancement of Nrf2 degradation by proteasomes conferring tight regulation on the response. Electrophiles act to counteract sequestration of Nrf2 by Keap1 and provoke Nrf2 activation. Constitutive activation of Nrf2-regulated transcription in Keap1 knockout mice clearly demonstrated that the disruption of Keap1 repression is sufficient for the activation of Nrf2. These observations indicated that the mechanism that modulates Nrf2-Keap1 interaction is pivotal for the cellular sensing mechanism for electrophiles. Recent analyses argue that the redox mechanism that modifies cysteine residues of Keap1 governs the Keap1-Nrf2 interaction and therefore is critical for sensing of electrophiles.