RT Journal Article
SR Electronic
T1 Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 832279
DO 10.1101/832279
A1 Tigist Y Tamir
A1 Brittany M Bowman
A1 Megan J Agajanian
A1 Dennis Goldfarb
A1 Travis P Schrank
A1 Trent Stohrer
A1 Andrew E Hale
A1 Priscila F Siesser
A1 Seth J Weir
A1 Ryan M Murphy
A1 Kyle M LaPak
A1 Bernard E Weissman
A1 Nathaniel J Moorman
A1 M. Ben Major
YR 2019
UL http://biorxiv.org/content/early/2019/11/05/832279.abstract
AB NFE2L2/NRF2 is a transcription factor and master regulator of cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, and conversely NRF2 protein levels as well as activity is diminished with age and in neurodegenerative disorders. Though NRF2 activating drugs are clinically beneficial, NRF2 inhibitors do not yet exist. Here we used a gain-of-function genetic screen of the kinome to identify new druggable regulators of NRF2 signaling. We found that the understudied protein kinase Brain Specific Kinase 2 (BRSK2) and the related BRSK1 kinases suppress NRF2-dependent transcription and NRF2 protein levels in an activity-dependent manner. Integrated phosphoproteomics and RNAseq studies revealed that BRSK2 drives AMPK activation and suppresses mTOR signaling. As a result, BRSK2 kinase activation suppressed ribosome-RNA complexes, global protein synthesis, and NRF2 protein levels. Collectively, our data establish the catalytically active BRSK2 kinase as a negative regulator of NRF2 via the AMPK/mTOR signaling. This signaling axis may prove useful for therapeutically targeting NRF2 in human diseases.Summary Statement BRSK2 suppresses NRF2 signaling by inhibiting protein synthesis through mTOR downregulation.