KEAP1
Protein-coding gene in the species Homo sapiens
From Wikipedia, the free encyclopedia
Kelch-like ECH-associated protein 1 is an E3 ubiquitin ligase that in humans is encoded by the Keap1 gene.[5]
Structure
Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 residue, which is one of the important cysteines in stress sensing. The intervening region (IVR) domain contains two critical cysteine residues, Cys273 and Cys288, which are a second group of cysteines important for stress sensing. A double glycine repeat (DGR) and C-terminal region domains collaborate to form a β-propeller structure, which is where Keap1 interacts with Nrf2.
Function
Keap1 functions as a negative regulator of Nrf2, a master regulator of the cellular antioxidant response that contributes to protection against oxidative stress.[6][7][8]
Under quiescent conditions, Nrf2 is retained in the cytoplasm through association with Keap1, which promotes ubiquitination and subsequent proteolysis of Nrf2. This sequestration and degradation mechanism mediates repression of Nrf2-dependent transcriptional activity.
Keap1 has been characterized as both a tumor suppressor gene and a metastasis suppressor gene.[9]
Interactions
Keap1 has been shown to interact with Nrf2.[6][7][8]
Several studies have identified an autoregulatory circuit linking KEAP1 and NRF2 expression. In mouse Keap1 (INrf2), Lee and colleagues identified an antioxidant response element (ARE) located on the negative strand that links Nrf2 activation to Keap1 transcription.[10]
Analysis of NRF2 occupancy in human lymphocytes identified an approximately 700 bp region within the KEAP1 promoter as highly enriched for NRF2 binding.[11]
These findings support reciprocal regulation between NRF2 and KEAP1. NRF2-driven KEAP1 expression has subsequently been characterized in human cancers, particularly squamous cell cancers, providing additional insight into regulation of NRF2 signaling.[12]
Clinical significance
Mutations
Mutations in KEAP1 that result in loss-of-function are not linked to familial cancers, though they do predispose individuals to multinodular goiters. The proposed mechanism leading to goiter formation is that the redox stress experienced when the thyroid produces hormones selects for loss of heterozygosity of KEAP1, leading to the goiters.[13]
As a drug target
Because Nrf2 activation leads to a coordinated antioxidant and anti-inflammatory response, and Keap1 represses Nrf2 activation, Keap1 has become a very attractive drug target.[14][15][16][17]
A series of synthetic oleane triterpenoid compounds, known as antioxidant inflammation modulators (AIMs), are being developed by Reata Pharmaceuticals, Inc. and are potent inducers of the Keap1-Nrf2 pathway, blocking Keap1-dependent Nrf2 ubiquitination and leading to the stabilization and nuclear translocation of Nrf2 and subsequent induction of Nrf2 target genes.[citation needed] The lead compound in this series, bardoxolone methyl (also known as CDDO-Me or RTA 402), was in late-stage clinical trials for the treatment of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus and showed an ability to improve markers of renal function in these patients.[citation needed] However, the Phase 3 trial was halted due to safety concerns.
