Molecular characterization of BRSK2 and BRSK1 kinases as negative regulators of the NRF2 transcription factor. Molecular characterization of BRSK2 and BRSK1 kinases as negative regulators of the NRF2 transcription factor

We found that the understudied Brain Specific Kinase 2 and 1 (BRSK2/1) proteins suppress NRF2-dependent transcription and NRF2 protein levels in a kinase-dependent fashion. Integrative phosphoproteomic screens, RNAseq profiling and follow-up validation studies revealed BRSK2/1-driven activation of AMPK and suppression of MTOR signaling. BRSK2 over-expression suppressed global protein synthesis and decreased ribosome-RNA associations, which results in decreased NRF2 protein levels. Overall, our data establish the BRSK1 and BRSK2 kinases as negative regulators of NRF2 via the AMPK/MTOR signaling axis. Overall design: Evaluation of BRSK2/1 induced changes in RNA via overexpression in HEK293Ts.