Abstract
Artemisitene (ATT) activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) by increasing its stabilization and reducing ubiquitination. The cysteine (Cys) residues of the cytosolic Nrf2 repressor Kelch-like ECH-associated protein-1 (Keap1) function as redox sensors and may be crucial in activating Nrf2. To determine whether ATT-induced Nrf2 activation is dependent on the modification of Keap1 and to elucidate the underlying mechanism, we transfected cell lines with six different Keap1 mutant constructs, each with a Cys (-77, -151, -257, -273, -288, and -297) to Ser substitution. Only the Cys151Ser mutant prevented ATT-mediated activation of Nrf2, indicating that the Cys151 residue of Keap1 likely interacts with ATT and is essential for Nrf2 stabilization and transcription of downstream genes. Our finding provides a pharmacological basis for using artemisitene against oxidative stress-related diseases.