Background
KEAP1, also known as Kelch-like ECH-associated protein 1, is a crucial regulator in cellular antioxidant defense. It is a cytoplasmic and nuclear protein that plays a key role in controlling the activity of the NRF2 (Nuclear factor erythroid 2-related factor 2) transcription factor. KEAP1 acts as a cytosolic inhibitor of NRF2 by facilitating its degradation through the ubiquitin-proteasome pathway. The KEAP1 protein structure consists of several functional domains, including one BTB (Broad-Complex, Tramtrack, and Bric-a-brac) or POZ (Poxvirus and Zinc finger) domain, one BACK (BTB and C-terminal Kelch) domain, and six Kelch repeats. It is broadly expressed in various tissues, with the highest levels found in skeletal muscle.
Under normal or basal conditions, KEAP1 binds to NRF2, sequestering it in the cytoplasm and preventing its translocation into the nucleus. This interaction leads to the ubiquitination of NRF2 by a complex involving KEAP1, CUL3 (Cullin 3), and RBX1 (RING-box protein 1), resulting in rapid NRF2 degradation. As a result, NRF2's transcriptional activity is suppressed, and the expression of genes involved in antioxidant defense, such as detoxifying enzymes, is repressed. However, KEAP1 function is dynamically regulated in response to oxidative stress and electrophilic compounds. Various inducers can modify specific cysteine residues within KEAP1, leading to the disruption of the KEAP1-NRF2 interaction. This modification prevents NRF2 ubiquitination and degradation, allowing NRF2 to accumulate and translocate into the nucleus. Once in the nucleus, NRF2 binds to the Antioxidant Response Element (ARE) and activates the expression of genes involved in antioxidant defense and detoxification processes.
Figure 1. Illustration of Keap1-Nrf2 pathway.
(Source: Suzuki, M. et al., 2016)
Anti-KEAP1 Polyclonal Antibody is a valuable tool used in scientific research to detect and study the expression and localization of the KEAP1 protein. It can be widely used in various research applications, including immunoblotting (Western blot), immunohistochemistry (IHC), immunofluorescence (IF), and immunoprecipitation (IP). Anti-KEAP1 Polyclonal Antibody allows researchers to detect and quantify KEAP1 protein levels, examine its cellular localization, and investigate its interactions with other proteins. This helps to understand the role of KEAP1 in cellular processes, such as oxidative stress response, antioxidant defense, and disease pathogenesis.
Alternative Names
Anti-kelch-like ECH-associated protein 1 Polyclonal Antibody
Anti-kelch-like protein 19 Polyclonal Antibody
Anti-INRF2 Polyclonal Antibody
Anti-cytosolic inhibitor of Nrf2 Polyclonal Antibody
References
- 1. Suzuki M, et al. Overview of redox regulation by Keap1–Nrf2 system in toxicology and cancer. Current Opinion in Toxicology. 2016, 1: 29-36.
References
2-Sulfonylpyridines as Tunable, Cysteine-Reactive Electrophiles
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Authors: Zambaldo, Claudio; Vinogradova, Ekaterina V.; Qi, Xiaotian; Iaconelli, Jonathan; Suciu, Radu M.; Koh, Minseob; Senkane, Kristine; Chadwick, Stormi R.; Sanchez, Brittany B.; Chen, Jason S.; Chatterjee, Arnab K.; Liu, Peng; Schultz, Peter G.; Cravatt, Benjamin F.; Bollong, Michael J.
Abstract
The emerging use of covalent ligands as chemical probes and drugs would benefit from an expanded repertoire of cysteine-reactive electrophiles for efficient and diverse targeting of the proteome. Here we use the endogenous electrophile sensor of mammalian cells, the KEAP1-NRF2 pathway, to discover cysteine-reactive electrophilic fragments from a reporter-based screen for NRF2 activation. This strategy identified a series of 2-sulfonylpyridines that selectively react with biological thiols via nucleophilic aromatic substitution (SNAr). By tuning the electrophilicity and appended recognition elements, we demonstrate the potential of the 2-sulfonylpyridine reactive group with the discovery of a selective covalent modifier of adenosine deaminase (ADA). Targeting a cysteine distal to the active site, this molecule attenuates the enzymatic activity of ADA and inhibits proliferation of lymphocytic cells. This study introduces a modular and tunable SNAr-based reactive group for targeting reactive cysteines in the human proteome and illustrates the pharmacological utility of this electrophilic series.
The emerging role of the Nrf2–Keap1 signaling pathway in cancer
Genes & Development
Authors: Jaramillo M C, Zhang D D.
Abstract
The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2 [Nrf2])–Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1) signaling pathway is one of the most important cell defense and survival pathways. Nrf2 can protect cells and tissues from a variety of toxicants and carcinogens by increasing the expression of a number of cytoprotective genes. As a result, several Nrf2 activators are currently being tested as chemopreventive compounds in clinical trials. Just as Nrf2 protects normal cells, studies have shown that Nrf2 may also protect cancer cells from chemotherapeutic agents and facilitate cancer progression. Nrf2 is aberrantly accumulated in many types of cancer, and its expression is associated with a poor prognosis in patients. In addition, Nrf2 expression is induced during the course of drug resistance. Collectively, these studies suggest that Nrf2 contributes to both intrinsic and acquired chemoresistance. This discovery has opened up a broad spectrum of research geared toward a better understanding of the role of Nrf2 in cancer. This review provides an overview of (1) the Nrf2–Keap1 signaling pathway, (2) the dual role of Nrf2 in cancer, (3) the molecular basis of Nrf2 activation in cancer cells, and (4) the challenges in the development of Nrf2-based drugs for chemoprevention and chemotherapy.
Keap1 degradation by autophagy for the maintenance of redox homeostasis
Proceedings of the National Academy of Sciences
Authors: Taguchi K, Fujikawa N, Komatsu M, et al.
Abstract
The Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system is essential for cytoprotection against oxidative and electrophilic insults. Under unstressed conditions, Keap1 serves as an adaptor for ubiquitin E3 ligase and promotes proteasomal degradation of Nrf2, but Nrf2 is stabilized when Keap1 is inactivated under oxidative/electrophilic stress conditions. Autophagy-deficient mice show aberrant accumulation of p62, a multifunctional scaffold protein, and develop severe liver damage. The p62 accumulation disrupts the Keap1-Nrf2 association and provokes Nrf2 stabilization and accumulation. However, individual contributions of p62 and Nrf2 to the autophagy-deficiency–driven liver pathogenesis have not been clarified. To examine whether Nrf2 caused the liver injury independent of p62, we crossed liver-specific Atg7::Keap1-Alb double-mutant mice into p62- and Nrf2-null backgrounds. Although Atg7::Keap1-Alb::p62-/- triple-mutant mice displayed defective autophagy accompanied by the robust accumulation of Nrf2 and severe liver injury, Atg7::Keap1-Alb::Nrf2-/- triple-mutant mice did not show any signs of such hepatocellular damage. Importantly, in this study we noticed that Keap1 accumulated in the Atg7- or p62-deficient mouse livers and the Keap1 level did not change by a proteasome inhibitor, indicating that the Keap1 protein is constitutively degraded through the autophagy pathway. This finding is in clear contrast to the Nrf2 degradation through the proteasome pathway. We also found that treatment of cells with tert-butylhydroquinone accelerated the Keap1 degradation. These results thus indicate that Nrf2 accumulation is the dominant cause to provoke the liver damage in the autophagy-deficient mice. The autophagy pathway maintains the integrity of the Keap1-Nrf2 system for the normal liver function by governing the Keap1 turnover.
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