Covalent Targeting of the SKP1-βTrCP Interface Activates NRF1/2 Signaling

The cap’n’collar family of bZIP transcription factors, including NRF1 and NRF2, execute essential protective transcriptional programs in response to cellular stressors and are thus of high interest to harness with pharmacological tools. From a high throughput screen of a covalently acting small molecule library, we identified the furanyl-acrylamide, exemplified by analog WC1, as a chemical scaffold capable of activating both NRF1 and NRF2 transcription programs. Chemical proteomic guided target identification work indicated that WC1 covalently modifies C160 of SKP1, an adaptor protein of the SKP1-CUL1-F-box E3 ubiquitin ligase complex, leading to decreased interactions with the F-box protein βTrCP, a shared regulator of NRF1 and NRF2 ubiquitination. This work identifies a novel mechanism of action to concurrently activate the NRF1 and NRF2 transcriptional programs and suggests a potential pharmacological route toward programming the activities of F-box containing proteins.