Nrf1-dependent Proteotoxic Stress Response

Nrf1 依赖性蛋白毒性应激反应

基本信息

批准号：
10576602
负责人：
Senthil Kumar Radhakrishnan
金额：
$ 6.76万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10576602
关键词：
Acetylation Antioxidants Aspartic Endopeptidases Autophagocytosis 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 Light Malignant Neoplasms Mammals Mass Spectrum Analysis Mediating Mediator of activation protein Membrane Methods Molecular Molecular Chaperones Motion Mutagenesis N-terminal Neurodegenerative Disorders Nuclear 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 base biological adaptation to stress cancer cell chromatin immunoprecipitation 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质毒性应激或蛋白酶体抑制抑制剂在运动中设定了一种指导DE的进化保守途径蛋白酶体的Novo合成作为补偿性反应。我们以前的研究在此应力响应途径中建立了转录因子NRF1作为关键参与者。 NRF1，通过与通常在蛋白酶体基因的调节区域，诱导其表达蛋白酶体抑制。作为内质网（ER） - 绑定转录因子，其在管腔中的大部分多肽，NRF1激活涉及其转化转换为胞质溶胶的方式取决于ATPase P97/VCP。接下来是蛋白水解处理和随后的转录活性形式的动员 NRF1到核。对NRF1途径的进一步了解可能会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途径激活的机理并探索各种有助于的因素从ER的管腔一直到核动员了这种转录因子。使用从上述两个目标中收集的信息，并使用遗传和化学在第三个目的中，我们建议测试NRF1途径的抑制是否导致增加的工具蛋白酶体抑制剂在癌细胞中的功效。因此，提议的线工作不仅重要的是从促进NRF1生物学的基础研究立场上很重要。它从转化的角度也很重要，因为它有潜力阐明新型策略以调节各种细胞蛋白清除途径人类疾病。