Abstract
The Kelch-like ECH associated protein 1 (Keap1) is a component of a Cullin3-based Cullin-RING E3 ubiquitin ligase (CRL) multisubunit protein complex. Within the CRL, homodimeric Keap1 functions as the Cullin3 adaptor, and importantly, it is also the critical component of the E3 ligase that performs the substrate recognition. The best-characterized substrate of Keap1 is transcription factor NF-E2 p45-related factor 2 (Nrf2), which orchestrates an elaborate transcriptional program in response to environmental challenges caused by oxidants, electrophiles and pro-inflammatory agents, allowing adaptation and survival under stress conditions. Keap1 is equipped with reactive cysteine residues that act as sensors for endogenously produced and exogenously encountered small molecules (termed inducers), which have a characteristic chemical signature, reactivity with sulfhydryl groups. Inducers modify the cysteine sensors of Keap1 and impair its ability to target Nrf2 for ubiquitination and degradation. Consequently, Nrf2 accumulates, enters the nucleus and drives the transcription of its target genes, which encode a large network of cytoprotective proteins. Here we summarize the early studies leading to the prediction of the existence of Keap1, followed by the discovery of Keap1 as the main negative regulator of Nrf2. We then describe the available structural information on Keap1, its assembly with Cullin3, and its interaction with Nrf2. We also discuss the multiple cysteine sensors of Keap1 that allow for detection of a wide range of endogenous and environmental inducers, and provide fine-tuning and tight control of the Keap1/Nrf2 stress-sensing response.
Highlights
Mammalian cells have evolved elaborate mechanisms for protection against environmental challenges, including those caused by exposure to oxidants, electrophiles and pro-inflammatory agents, which are involved in the pathogenesis of almost all chronic disease and ageing
This review focuses on Kelch-like ECH associated protein 1 (Keap1), which functions as a substrate adaptor protein for the degradation of NF-E2 p45-related factor 2 (Nrf2) and serves as an intracellular sensor for inducers, by utilising a number of reactive cysteine residues
There is no longer any scepticism regarding the existence in the cell of ‘ ... a protein endowed with highly reactive cysteine residue(s) that serves as the sensor for small-molecule inducers of the phase 2 response’
Summary
Mammalian cells have evolved elaborate mechanisms for protection against environmental challenges, including those caused by exposure to oxidants, electrophiles and pro-inflammatory agents, which are involved in the pathogenesis of almost all chronic disease and ageing Deficiencies in these protective mechanisms are associated with increased disease risk and accelerated disease progression. Attributed to specific phytochemicals, which are able to induce defence systems in mammalian cells Induction of these natural defences is protective against damage and allows adaptation and survival under conditions of stress. Depending on the specific conditions, such as the presence or absence of growth factors or endoplasmic reticulum (ER) stress, the process of Nrf degradation is mediated by several ubiquitin ligase systems, including Kelch-like ECH associated protein 1 (Keap1) [3], a substrate adaptor protein for Cullin3-based. This review focuses on Keap, which functions as a substrate adaptor protein for the degradation of Nrf and serves as an intracellular sensor for inducers, by utilising a number of reactive cysteine residues
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