Small-Molecule Stimulators of NRF1 Transcriptional Activity
Small-Molecule Stimulators of NRF1 Transcriptional Activity
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DOI：
10.1002/cbic.201900487
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发表时间：
2019-11-08
期刊：
影响因子：
3.2
通讯作者：
Bollong, Michael J.
中科院分区：
文献类型：
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作者：
Iaconelli, Jonathan;Ibrahim, Lara;Bollong, Michael J.
转录因子核因子红系2相关因子1(NRF1)通过刺激蛋白酶体亚基和一系列保护酶的转录来维持蛋白稳定并促进细胞的弹性。尽管NRF1的激活在一些疾病状态下可能是有益的，但关于它的配基和上游调控的信息还很缺乏。在这里，我们报告了一种高通量的化学筛选，它鉴定了NRF1驱动的转录的选择性刺激物，包括未注释的泛素蛋白酶体系统(UPS)的抑制剂以及两个非UPS靶标化合物，它们在次极大UPS抑制的背景下协同激活NRF1。这项工作引入了一套工具分子来研究NRF1的转录反应，并揭示了控制细胞中NRF1活性的可药物成分。
The transcription factor nuclear factor erythroid 2-related factor 1 (NRF1) maintains proteostasis and promotes cellular resilience by stimulating the transcription of proteasomal subunits and a host of protective enzymes. Although NRF1 activation would likely be beneficial in a number of disease states, information regarding its ligandability and upstream regulation are lacking. Herein we report a high-throughput chemical screen that identified selective stimulators of NRF1-driven transcription, including unannotated inhibitors of the ubiquitin proteasome system (UPS) as well as two non-UPS-targeted compounds that synergistically activate NRF1 in the context of submaximal UPS inhibition. This work introduces a suite of tool molecules to study the NRF1 transcriptional response and to uncover the druggable components governing NRF1 activity in cells.