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.

核因子红细胞 2 相关因子 2（NFE2L2，也称为 NRF2）是一种转录因子，是细胞抗氧化反应的主要调节因子。异常高的 NRF2 依赖性转录在人类癌症中反复出现，但相反，NRF2 活性随着年龄以及神经退行性和代谢性疾病而减弱。尽管NRF2激活药物在临床上有益，但NRF2抑制剂尚不存在。在这里，我们描述了使用激酶组的功能获得性遗传筛选来识别 NRF2 信号传导的新的可药物调节因子。我们发现，正在研究的蛋白激酶脑特异性激酶 2 (BRSK2) 和相关的 BRSK1 激酶以活性依赖性方式抑制 NRF2 依赖性转录和 NRF2 蛋白水平。综合磷酸蛋白质组学和 RNAseq 研究表明，BRSK2 驱动 5'-AMP 激活的蛋白激酶 α2 (AMPK) 信号传导并抑制 mTOR 通路。因此，BRSK2 激酶激活会抑制核糖体-RNA 复合物、整体蛋白质合成和 NRF2 蛋白质水平。总的来说，我们的数据阐明了 BRSK2 和 BRSK1 激酶，部分是通过将它们与 NRF2 信号传导和 mTOR 功能连接起来。该信号轴可能对治疗人类疾病中的 NRF2 有用。

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