Electrophilic nitro-fatty acids activate NRF2 by a KEAP1 cysteine 151-independent mechanism

KANSANEN E, BONACCI G, SCHOPFER FJ, KUOSMANEN SM, TONG KI, LEINONEN H, WOODCOCK SR, YAMAMOTO M, CARLBERG C, YLÄ-HERTTUALA S, FREEMAN BA, LEVONEN AL.

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Año: 2011 vol. 286 p. 14019 - 14019

itro-fatty acids (NO2-FAs) are electrophilic signaling mediators formed in vivo via nitric oxide (NO)- and nitrite (NO2-)-dependent reactions. Nitro-fatty acids modulate signaling cascades via reversible covalent post-translational modification of nucleophilic amino acids in regulatory proteins and enzymes, thus altering downstream signaling events, such as Keap1-Nrf2-antioxidant response element (ARE)-regulated gene expression. In this study, we investigate the molecular mechanisms by which 9- and 10-nitro-octadec-9-enoic acid (OA-NO2) activate the transcription factor Nrf2, focusing on the post-translational modifications of cysteines in the Nrf2 inhibitor Keap1 by nitroalkylation and its downstream responses. Of the two regioisomers, 9-nitro-octadec-9-enoic acid was a more potent ARE inducer than 10-nitro-octadec-9-enoic acid. The most OA-NO2-reactive Cys residues in Keap1 were Cys(38), Cys(226), Cys(257), Cys(273), Cys(288), and Cys(489). Of these, Cys(273) and Cys(288) accounted