Proteolytic Control of Iron Metabolism by the E3 Ubiquitin Ligase FBXL5

摘要 真核细胞已经建立了一个基于E3的强大的细胞内铁稳态调节系统 泛素连接酶FBXL5及其对铁调节蛋白1和2的降解在较早的资助期， 我们建立了一个范例，其中FBXL5充当整合不同生理信号的信号中枢 协调IRP介导的下游基因表达程序。此应用程序在此基础上构建 为了研究信号如何通过Fe-S簇组装、氧代谢和细胞周期途径 调整FBXL5-IRP轴。具体目标1侧重于定义氧依赖的机制 FBXL5与CIA靶向复合体的相互作用调节IRP的降解。在特定目标2中，我们测试 假设FBXL5降解E3泛素连接酶pVHL调节细胞对低氧的反应。 《特定目标3》中的实验将检验FBXL5和细胞周期进展通路之间的相互作用 来协调细胞增殖和新陈代谢。加在一起，这三个目标将揭示分子 控制FBXL5如何集成和解释通过多个信令传递的信号的机制 以决定细胞对铁可利用性的多方面反应。

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.