Nrf1-dependent Proteotoxic Stress Response

Nrf1 依赖性蛋白毒性应激反应

基本信息

批准号：
10725084
负责人：
Senthil Kumar Radhakrishnan
金额：
$ 1.69万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725084
关键词：
Acetylation Antioxidants Aspartic Endopeptidases Autophagocytosis Autophagosome Basic Science Binding Biological Assay Biology Cancer cell line Cell Nucleus Cells Chemicals Clip Co-Immunoprecipitations Cytosol DNA Binding Data EP300 gene Endoplasmic Reticulum Ensure Erythroid Feedback Foundations Genes Genetic Genetic Transcription Glean HDAC1 gene HDAC2 gene Histone Deacetylase Human Human Pathology Knowledge Lead Malignant Neoplasms Mammals Mass Spectrum Analysis Mediating Mediator Membrane Methods Molecular Molecular Chaperones Motion Mutagenesis N-terminal Neurodegenerative Disorders Nuclear Nuclear Extract Nucleic Acid Regulatory Sequences Organism Output Pathway interactions Peptide Hydrolases Positioning Attribute Process Proteasome Inhibition Proteasome Inhibitor Proteins Proteolytic Processing Proteomics Publishing Recovery Regulation Response Elements Role Route Shapes Stress Testing Transcript Transcriptional Activation Transferase Transmembrane Domain Work Yeasts attenuation biological adaptation to stress cancer cell chromatin immunoprecipitation cofactor coping experience experimental study human disease inhibitor therapy loss of function multicatalytic endopeptidase complex novel strategies p97 ATPase polypeptide promoter protein degradation proteotoxicity response therapeutic target tool transcription factor transcriptome sequencing valosin-containing protein

项目摘要

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.

抽象的蛋白酶体对细胞蛋白酶体活性的蛋白毒性应激或抑制抑制剂药物启动了一条进化上保守的途径，指导 de 蛋白酶体的新合成作为补偿反应。我们之前的研究确立了转录因子 Nrf1 作为该应激反应途径的关键角色。 Nrf1 能够与通常存在于体内的抗氧化反应元件结合蛋白酶体基因的调节区域，诱导其表达以响应蛋白酶体抑制。作为内质网 (ER) 结合转录因子 Nrf1 的大部分多肽位于管腔中，Nrf1 的激活涉及其逆转录转位到以依赖于 ATP 酶 p97/VCP 的方式进入细胞质。接下来是转录活性形式的蛋白水解加工和随后的动员 Nrf1 至细胞核。对 Nrf1 通路的进一步了解可以揭示细胞应对蛋白毒性应激的复杂机制。在前两个目标中，我们建议剖析功能输出和 Nrf1通路激活机制并探索各种辅助因素将这种转录因子从内质网腔一直调动到细胞核。利用从上述两个目标收集的信息并利用遗传和化学方法工具，在第三个目标中，我们建议测试 Nrf1 通路的抑制是否会导致增加蛋白酶体抑制剂治疗癌细胞的功效。因此，建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很重要；它从翻译的角度来看也很重要，因为它有潜力阐明调节各种细胞蛋白质清除途径的新策略人类疾病。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy.

转录因子 Nrf1 调节蛋白毒性应激诱导的自噬。

DOI：
10.1083/jcb.202306150
发表时间：
2024
期刊：
The Journal of cell biology
影响因子：
0
作者：
Ward,MadisonA;Vangala,JanakiramR;KamberKaya,HatemElif;Byers,HollyA;Hosseini,Nayyerehalsadat;Diaz,Antonio;Cuervo,AnaMaria;Kaushik,Susmita;Radhakrishnan,SenthilK
通讯作者：
Radhakrishnan,SenthilK

BET Inhibitors Synergize with Carfilzomib to Induce Cell Death in Cancer Cells via Impairing Nrf1 Transcriptional Activity and Exacerbating the Unfolded Protein Response.

BET 抑制剂与卡非佐米协同作用，通过损害 Nrf1 转录活性和加剧未折叠蛋白反应来诱导癌细胞死亡。