Regulation of transcription factors NRF2 and HSF1 in mediating cellular stress responses
type: CreativeWork
description: The KEAP1/NRF2/ARE pathway is at the forefront of cellular defense. Induction of this pathway is protective against various conditions of stress such as oxidative stress and exposure to electrophiles. Conversely, failure to upregulate the pathway leads to increased disease susceptibility and accelerated pathogenesis. Under basal conditions, transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) is targeted for ubiquitination and proteasomal degradation by a repressor protein Kelch-like (ECH)-associated protein (KEAP1), a substrate adaptor for Cullin 3-based E3 ubiquitin ligase. Inducers of the pathway chemically modify specific cysteines within KEAP1, leading to loss of repressor function, NRF2 accumulation and enhanced transcription of genes encoding a large network of cytoprotective proteins. The cyanoenones are the most potent NRF2 activators known. Cyanoenones bind to KEAP1 covalently and reversibly, and are suitable for chronic in vivo administration. However, the cysteine sensor for these compounds is unknown. Among the cysteine sensors of KEAP1, C151 in the BTB domain and C273 and C288 in the intervening region, are best characterized. In this study using KEAP1-knockout mouse embryonic fibroblasts (MEFs) rescued with wild-type (WT) KEAP1 or cysteine mutants, we tested a series of cyanoenones for their ability to modify specific cysteine sensors in KEAP1. We discovered that remarkably, all compounds of this class specifically target C151 regardless of their molecular shape or size. In addition, primary peritoneal macrophages (PMφ) derived from KEAP1C151S/C151S knock-in mice generated using the CRISPR/Cas9 technology, had higher LPS-induced inflammatory responses than cells from WT animals. Furthermore, at nanomolar concentrations, the tricyclic cyanoenone TBE-31 strongly suppresses LPS-induced inflammatory responses in primary PMφ cells, suggesting the potential for therapeutic use in inflammatory diseases. Another cytoprotective response …
abstract: The KEAP1/NRF2/ARE pathway is at the forefront of cellular defense. Induction of this pathway is protective against various conditions of stress such as oxidative stress and exposure to electrophiles. Conversely, failure to upregulate the pathway leads to increased disease susceptibility and accelerated pathogenesis. Under basal conditions, transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) is targeted for ubiquitination and proteasomal degradation by a repressor protein Kelch-like (ECH)-associated protein (KEAP1), a substrate adaptor for Cullin 3-based E3 ubiquitin ligase. Inducers of the pathway chemically modify specific cysteines within KEAP1, leading to loss of repressor function, NRF2 accumulation and enhanced transcription of genes encoding a large network of cytoprotective proteins. The cyanoenones are the most potent NRF2 activators known. Cyanoenones bind to KEAP1 covalently and reversibly, and are suitable for chronic in vivo administration. However, the cysteine sensor for these compounds is unknown. Among the cysteine sensors of KEAP1, C151 in the BTB domain and C273 and C288 in the intervening region, are best characterized. In this study using KEAP1-knockout mouse embryonic fibroblasts (MEFs) rescued with wild-type (WT) KEAP1 or cysteine mutants, we tested a series of cyanoenones for their ability to modify specific cysteine sensors in KEAP1. We discovered that remarkably, all compounds of this class specifically target C151 regardless of their molecular shape or size. In addition, primary peritoneal macrophages (PMφ) derived from KEAP1C151S/C151S knock-in mice generated using the CRISPR/Cas9 technology, had higher LPS-induced inflammatory responses than cells from WT animals. Furthermore, at nanomolar concentrations, the tricyclic cyanoenone TBE-31 strongly suppresses LPS-induced inflammatory responses in primary PMφ cells, suggesting the potential for therapeutic use in inflammatory diseases. Another cytoprotective response …
author: Dayalan Naidu, Sharadha
language: eng
date published: 2016
date modified: 2026-07-24T02:08:19Z
provider: University of Dundee
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Dundee