Abstract
NRF2 is a master regulator of cellular anti-oxidant and anti-inflammatory responses, and strategies to augment NRF2-dependent responses may beneficial in many diseases. Basal NRF2 protein level is constrained by constitutive KEAP1-mediated degradation, but in the presence of electrophiles, NRF2 ubiquitination is inhibited. Impeded NRF2 degradation increases NRF2 protein, resulting in up-regulation of anti-oxidant gene transcription, and decreased inflammation. KEAP1-independent mechanisms regulating NRF2 stability have also been reported. Here we employed an HTS approach and identified a small molecule, BC-1901S, that stabilized NRF2 and increased its activity. BC-1901S activated NRF2 by inhibiting NRF2 ubiquitination in a KEAP1-independent manner. It further increased NRF2-dependent anti-oxidant gene transcription, and exhibited anti-inflammatory effects in vitro and in vivo. Further, we identified a new NRF2-interacting partner, DDB1 and CUL4 Associated Factor 1 (DCAF1), an E3 ligase that targeted NRF2 for proteasomal degradation. Mechanistically, BC-1901S directly bound to DCAF1 and disrupted NRF2/DCAF1 interaction, thus activating NRF2. These findings provide new insights in NRF2 biology and NRF2 based anti-inflammatory therapy.
Highlights
Nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcription factor controlling cellular anti-oxidant responses [1,2]
NRF2 is a central regulator of cellular anti-oxidant and inflammatory responses, with a vast volume of literature describing its regulation and potential applicability to treat human disease [1,2,7,28]
Our main findings are: 1) BC-1901S is a novel NRF2 activator that prevents NRF2 protein degradation, 2.) BC-1901S exhibits anti-inflammatory effects in a murine model of LPSinduced acute lung injury, 3) BC-1901S operates in a Kelchlike ECH-Associated Protein 1 (KEAP1)-independent manner, 4) Identification of DDB1 and CUL4 Associated Factor 1 (DCAF1) as a new and potentially dominant NRF2 repressor, and 5) BC-1901S may function through inhibition of the DCAF1-NRF2 degradation axis
Summary
Nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcription factor controlling cellular anti-oxidant responses [1,2]. KEAP1 is an adapter protein in an E3 ubiquitin ligase complex involving CUL3 and RBX1, and directs the ubiquitination and degradation of NRF2 in the proteasome. In the presence of electrophiles generated by oxidative stress, KEAP1 dissociates with NRF2, increasing NRF2 protein abundance. NRF2 translocates to the nucleus and facilitates transcriptional upregulation of several anti-oxidant response element (ARE) genes [1,11]. In addition to KEAP1-dependent regulation, NRF2 is subjected to regulation through the ubiquitin-proteasome system by KEAP1-independent mechanisms. The E3 ligases DCAF11 [12], HRD1 [13], and β-TrCP [14] interact with NRF2 and regulate its abundance through ubiquitination and degradation in the proteasome
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