2. Academic Validation
  3. Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor

Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor

  • J Cell Sci. 2020 Jul 15;133(14):jcs241356. doi: 10.1242/jcs.241356.
Tigist Y Tamir 1,  Brittany M Bowman 2,  Megan J Agajanian 1,  Dennis Goldfarb 2 3 4,  Travis P Schrank 2,  Trent Stohrer 2 5,  Andrew E Hale 6,  Priscila F Siesser 2,  Seth J Weir 2,  Ryan M Murphy 1,  Kyle M LaPak 3,  Bernard E Weissman 2 7,  Nathaniel J Moorman 2 6,  M Ben Major 8 2 3 9
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 2 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 3 Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • 4 Institute for Informatics, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • 5 Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 6 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • 7 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 8 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA [email protected].
  • 9 Department of Otolaryngology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
PMID: 32546533 DOI: 10.1242/jcs.241356
Abstract

Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) is a transcription factor and master regulator of cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human Cancer, but conversely NRF2 activity diminishes with age and in neurodegenerative and metabolic disorders. Although NRF2-activating drugs are clinically beneficial, NRF2 inhibitors do not yet exist. Here, we describe use of a gain-of-function genetic screen of the kinome to identify new druggable regulators of NRF2 signaling. We found that the under-studied 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 5'-AMP-activated protein kinase α2 (AMPK) signaling and suppresses the mTOR pathway. As a result, BRSK2 kinase activation suppresses ribosome-RNA complexes, global protein synthesis and NRF2 protein levels. Collectively, our data illuminate the BRSK2 and BRSK1 kinases, in part by functionally connecting them to NRF2 signaling and mTOR. This signaling axis might prove useful for therapeutically targeting NRF2 in human disease.This article has an associated First Person interview with the first author of the paper.

Keywords

AMPK; BRSK1; BRSK2; Functional genomics; Kinase; NRF2; Oxidative stress response; Phosphoproteomics; mTOR.

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