Proteolytic Control of Iron Metabolism by the E3 Ubiquitin Ligase FBXL5

摘要 真核细胞已经建立了一个强大的系统，用于调节细胞内铁稳态的基础上E3 泛素连接酶FBXL 5及其对铁调节蛋白1和2（IRP）的降解。在较早的供资期间， 我们建立了一个范例，其中FBXL 5作为信号中枢，整合了不同的生理信号， 以协调下游IRP介导的基因表达程序。本应用程序建立在此基础上 研究通过Fe-S簇组装、氧代谢和细胞周期途径的信号传导 调节FBXL 5-IRP轴。具体目标1侧重于定义O2依赖性 FBXL 5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FBXL 5降解E3泛素连接酶pVHL调节细胞对缺氧的反应。 具体目标3中的实验将检查FBXL 5与细胞周期进展途径之间的相互作用 以协调细胞增殖和新陈代谢。这三个目标将共同揭示 控制FBXL 5如何整合和解释通过多种信号转导的信号的机制 途径，以决定对铁可用性的多方面细胞反应。

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.