Molecular Basis of the KEAP1-NRF2 Signaling Pathway

Abstract

Transcription factor NRF2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. NRF2 induces expression of detoxification and antioxidant enzymes and suppresses inductions of pro-inflammatory cytokine genes. KEAP1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of CULLIN 3 (CUL3)-based E3 ubiquitin ligase. KEAP1 regulates the activity of NRF2 and acts as a sensor for oxidative and electrophilic stresses. NRF2 has been found to be activated in many types of cancers with poor prognosis. Therapeutic strategies to control NRF2-overeactivated cancers have been considered not only by targeting cancer cells with NRF2 inhibitors or NRF2 synthetic lethal chemicals, but also by targeting host defense with NRF2 inducers. Understanding precise molecular mechanisms how the KEAP1-NRF2 system senses and regulates the cellular response is critical to overcome intractable NRF2-activated cancers.

TRIM21 silencing inhibits the apoptosis and expedites the osteogenic differentiation of dexamethasone‑induced MC3T3‑E1 cells by activating the Keap1/Nrf2 pathway

“…The expression of Keap1/Nrf2 pathway-related proteins was investigated by the present study because the Keap1/Nrf2 pathway was shown to play an inhibitory role in oxidative stress ( 17 ). The decreased Nrf2, HO-1 and NQO1 expression and the increased Keap1 expression in Dex-challenged MC3T3-E1 cells were all restored after TRIM21 was knocked down ( Fig.…”

Regulation of NRF2 by Phosphoinositides and Small Heat Shock Proteins

“…NRF2 is activated and translocates to the nucleus in response to cellular stress, especially oxidative stress 19–22 . Consistent with these reports, NRF2 expression was dramatically increased by genotoxic stress (Cisplatin), NRF2 induction (tBHQ and Sulforaphane), and oxidative stress (Diethyl maleate, DEM), and the SOD1 inhibitor LCS-1 (Extended data Fig.1b).…”

Arginine deprivation enriches lung cancer proteomes with cysteine by inducing arginine-to-cysteine substitutants

“…KEAP1 is a cysteine-rich protein, of which a few residues (C151, C226, C273, C288, and C622/624) are oxidized in response to electrophiles, oxidative stimuli, and toxins, linking KEAP1 to redox homeostasis. 58 , 59 These cysteines are functionally important to control KEAP1 activity, as their modification results in the nuclear accumulation of NRF2 and the induction of downstream target genes involved in antioxidation responses. In addition, NRF2 pathway activation elevates SLC7A11, a glutamine/C2 antiporter, 37 , 38 , 39 and KEAP1 mutations stimulate the accumulation of intracellular cysteine levels.…”