Nrf1-dependent Proteotoxic Stress Response

摘要 蛋白酶体对细胞蛋白酶体活性的抑制或蛋白毒性应激 抑制剂药物启动了一条进化上保守的途径，引导De 蛋白酶体的新合成作为一种代偿反应。我们之前的研究 确定转录因子Nrf1在这一应激反应途径中起关键作用。 NRF1，通过它与通常存在于 蛋白酶体基因的调节区，诱导它们的表达 蛋白酶体抑制。作为内质网(ER)结合的转录因子 Nrf1的大部分多肽在管腔中，Nrf1的激活涉及到它的逆转位到 胞浆的形成依赖于ATPase p97/VCP。这之后是 蛋白水解性加工和随后的转录活性形式的动员 NRF1到细胞核。对Nrf1通路的进一步了解可能有助于揭示 细胞应对蛋白毒性应激的复杂机制。 在前两个目标中，我们建议剖析函数输出和 Nrf1途径的激活机制及多种因素的探讨 将这个转录因子从内质网的管腔一直动员到细胞核。 利用从上述两个目的收集的信息，并使用遗传和化学 工具，在第三个目标中，我们建议测试抑制Nrf1通路是否会导致 蛋白酶体抑制剂治疗癌细胞的疗效。因此，拟议的线路 这项工作不仅从促进NRF1生物学的基础研究角度来看是重要的；它 从翻译的角度来看也很重要，因为它有可能 阐明新的策略来调节细胞蛋白质清除途径在不同的 人类疾病。

ABSTRACT Proteotoxic stress or inhibition of cellular proteasome activity by proteasome inhibitor drugs sets in motion an evolutionarily conserved pathway that directs the de novo synthesis of proteasomes as a compensatory response. Our previous studies established the transcription factor Nrf1 as a key player in this stress-response pathway. Nrf1, by its ability to bind to the anti-oxidant response elements typically found in the regulatory regions of proteasome genes, induces their expression in response to proteasome inhibition. As an endoplasmic reticulum (ER)-bound transcription factor with a bulk of its polypeptide in the lumen, Nrf1 activation involves its retrotranslocation into the cytosol in a manner that depends on the ATPase p97/VCP. This is followed by proteolytic processing and subsequent mobilization of the transcriptionally active form of Nrf1 to the nucleus. Further understanding of the Nrf1 pathway could shed light on the intricate mechanisms by which cells cope with proteotoxic stress. In the first two aims, we propose to dissect the functional output and the mechanism of activation of Nrf1 pathway and explore various factors that assist in mobilizing this transcription factor from the lumen of the ER all the way to the nucleus. Using the information gleaned from the above two aims and using genetic and chemical tools, in the third aim, we propose to test if inhibition of Nrf1 pathway leads to increased efficacy of proteasome inhibitor treatment in cancer cells. Thus, the proposed line of work is important not only from a basic research stand-point of furthering Nrf1 biology; it is also significant from a translational perspective as well, since it has the potential to illuminate novel strategies to modulate the cellular protein clearance pathways in various human diseases.