KEAP1 gene

The KEAP1 gene (KEAP1 stands for: Kelch Like ECH Associated Protein 1) is a protein-coding gene located on chromosome 19p13.2. Two alternatively spliced transcript variants encoding the same isoform have been found for this gene. Related signaling pathways include class I MHC-mediated antigen processing and presentation and infectious diseases.

The KEAP1 gene encodes a protein, Kelch Like ECH Associated Protein 1, which contains KELCH-1-like domains and a BTB/POZ domain. The encoded Kelch-like ECH-associated protein 1 interacts with the NF-E2-related factor 2 in a redox-sensitive manner. Dissociation of the proteins in the cytoplasm is followed by transport of the NF-E2-related factor 2 into the nucleus. This interaction leads to the expression of the catalytic subunit of gamma-glutamylcysteine synthetase.

Kelch Like ECH Associated Protein 1 (KEAP1) is a substrate-specific adaptor of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination (Zhang DD et al. 2003).

KEAP1 acts as a key sensor for oxidative and electrophilic stress: Under normal conditions, the BCR(KEAP1) complex mediates the ubiquitination and degradation of NFE2L2/NRF2, a transcription factor that regulates the expression of many cytoprotective genes (Eggler AL et al. 2005).

In response to oxidative stress, various electrophilic metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivation of the ubiquitin ligase activity of the BCR(KEAP1) complex and promoting the accumulation of NFE2L2/NRF2 in the nucleus and the expression of phase II detoxification enzymes (Mills EL et al. 2018). In response to selective autophagy, KEAP1 is sequestered in inclusion bodies after its interaction with SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2 (Jain A et al. 2010). The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, which increases the sequestration activity and degradation of SQSTM1/p62. The BCR(KEAP1) complex also directs BPTF and PGAM5 for ubiquitination and degradation by the proteasome.

Diseases associated with KEAP1 include goiter, multinodular 1, with or without Sertoli-Leydig cell tumors and squamous cell carcinoma.

1. Eggler AL et al. (2005) Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. Proc Natl Acad Sci U S A 102:10070-10075.
2. Mills EL et al. (2018) Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556(7699):113-117.
3. Jain A et al. (2010) p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem 285:22576-22591
4. Zhang DD et al. (2003) Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol 23:8137-8151.