Proteolytic Control of Iron Metabolism by the E3 Ubiquitin Ligase FBXL5

E3 泛素连接酶 FBXL5 对铁代谢的蛋白水解控制

基本信息

批准号：
10377928
负责人：
James Akira Wohlschlegel
金额：
$ 32.76万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377928
关键词：
Anemia Autophagocytosis Binding Biogenesis Biological Biological Process Cell Cycle Cell Cycle Progression Cell Cycle Progression Pathway Cell Proliferation Cells Complex Cues Data Defect Disease Ensure Enzymes Eukaryotic Cell Event Ferritin Foundations Funding G1 Phase G2 Phase Gene Expression Grant Hemochromatosis Homeostasis Hypoxia In Vitro Iron Iron Regulatory Protein 1 Iron-Binding Proteins Link Malignant Neoplasms Mediating Mediator of activation protein Messenger RNA Metabolism Mitosis Modeling Molecular Oxidative Stress Oxygen Pathogenesis Pathway interactions Physiological Play Proteins Publishing RNA-Binding Proteins Research Response Elements Role S phase Signal Pathway Signal Transduction Stress System TFRC gene Testing Toxic effect Trace metal Ubiquitin Ubiquitination Work base design experimental study insight iron metabolism metal transporting protein 1 mutant novel prevent programs protein complex protein expression response ubiquitin-protein ligase

项目摘要

Abstract Eukaryotic cells have established a robust system for regulating intracellular iron homeostasis based on the E3 ubiquitin ligase FBXL5 and its degradation of Iron Regulatory Proteins 1 and 2 (IRPs). In earlier funding periods, we established a paradigm in which FBXL5 acts as a signaling hub that integrates different physiological signals to coordinate the downstream IRP-mediated gene expression program. This application builds on that foundation to examine how signaling through the Fe-S cluster assembly, oxygen metabolism, and cell cycle pathways regulates the FBXL5-IRP axis. Specific aim 1 focuses on defining the mechanism by which the O2-dependent interaction of FBXL5 with the CIA targeting complex regulates IRP degradation. In specific aim 2, we test the hypothesis that degradation of the E3 ubiquitin ligase pVHL by FBXL5 regulates the response of cells to hypoxia. The experiments in specific aim 3 will examine the interplay between FBXL5 and cell cycle progression pathways to coordinate cell proliferation with metabolism. Together, these three aims will uncover the molecular mechanisms that govern how FBXL5 integrates and interprets signals transduced through multiple signaling pathways in order to dictate the multi-faceted cellular response to iron availability.

抽象的真核细胞已经建立了基于E3的强大的调节细胞内铁稳态的系统泛素连接酶 FBXL5 及其对铁调节蛋白 1 和 2 (IRP) 的降解。在早期的资助期间，我们建立了一个范例，其中 FBXL5 作为信号枢纽，整合不同的生理信号协调下游 IRP 介导的基因表达程序。该应用程序建立在该基础上研究信号传导如何通过 Fe-S 簇组装、氧代谢和细胞周期途径调节 FBXL5-IRP 轴。具体目标 1 侧重于定义 O2 依赖的机制 FBXL5 与 CIA 靶向复合物的相互作用调节 IRP 降解。在具体目标 2 中，我们测试假设 FBXL5 降解 E3 泛素连接酶 pVHL 可调节细胞对缺氧的反应。具体目标 3 中的实验将检查 FBXL5 与细胞周期进展途径之间的相互作用协调细胞增殖与新陈代谢。这三个目标共同将揭示分子控制 FBXL5 如何集成和解释通过多种信号转导的信号的机制途径来决定细胞对铁可用性的多方面反应。