Nrf1-dependent Proteotoxic Stress Response

摘要 蛋白毒性应激或蛋白酶体对细胞蛋白酶体活性的抑制 抑制剂药物启动了一条进化上保守的途径， 作为补偿反应的蛋白酶体的重新合成。我们以前的研究 建立了转录因子Nrf 1作为一个关键球员在这一压力反应途径。 Nrf 1通过其与抗氧化反应元件结合的能力，该元件通常存在于 蛋白酶体基因的调节区，诱导它们的表达， 蛋白酶体抑制作为一种内质网（ER）结合的转录因子， 在管腔中的大量多肽中，Nrf 1的激活涉及其逆转位到 细胞质中的一种方式，依赖于ATP酶p97/VCP。这之后是 蛋白水解加工和随后的转录活性形式的动员 Nrf 1到细胞核。对Nrf 1通路的进一步了解可能有助于阐明 细胞科普蛋白毒性应激的复杂机制。 在前两个目标中，我们建议剖析功能输出和 Nrf 1通路的激活机制，并探讨各种因素，帮助 将这种转录因子从内质网腔一路转移到细胞核。 利用从上述两个目标中收集的信息，并使用遗传和化学方法， 工具，在第三个目标中，我们建议测试Nrf 1通路的抑制是否会导致增加 蛋白酶体抑制剂治疗在癌细胞中的功效。因此，拟议的路线 这项工作不仅从促进Nrf 1生物学的基础研究角度来看很重要， 从翻译的角度来看也很重要，因为它有可能 阐明新的战略，以调节细胞蛋白质清除途径，在各种 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.