Cysteine-based molecular switches: a focus on KEAP1 and BACH1 in regulating the antioxidant response.

Abstract

Due to the chemical properties of their thiol groups and the surrounding amino acid environment, specific cysteines in proteins serve as the principal intracellular sensors for oxidants and electrophiles. In this review, we focus on the ubiquitin ligase substrate adaptor Kelch-like ECH-associated protein 1 (KEAP1) and the transcriptional repressor BTB and CNC homology 1 (BACH1) as representative cysteine-based molecular switches, both of which have critical functions in the cellular antioxidant response. KEAP1 is a protein endowed with a number of highly reactive cysteines, which can be covalently and preferentially modified by a wide array of reactive oxygen species, reactive nitrogen species and reactive electrophilic species, from endogenous as well as exogenous origin. Covalent cysteine modifications are also involved in the regulation of the localisation, stability and turnover of BACH1. Both KEAP1 and BACH1 antagonize the constitutively expressed transcription factor NF-E2 p45-related factor 2 (NRF2), the master regulator of the cellular antioxidant response, thus keeping the transcriptional activity of NRF2 low at homeostatic state. Cysteine modifications within KEAP1 and BACH1 render the repressor proteins inactive, resulting in rapid NRF2 activation that does not rely on de novo transcription of NFE2L2, the gene encoding NRF2. Consequently, NRF2 induces the transcriptional upregulation of a large network of genes encoding cytoprotective proteins, many of which have antioxidant functions, restoring the redox homeostasis.