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：
9306110
负责人：
James Akira Wohlschlegel
金额：
$ 30.04万
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 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9306110
关键词：
Alanine Amino Acids Anemia Autophagocytosis Binding Binding Proteins Biogenesis Biological Process Cell Respiration Cell physiology Cells Communication Complex Coupling DNA Repair DNA biosynthesis Data Defect Disease Ensure Enzymes Eukaryotic Cell Ferritin Foundations Gap Junctions Gene Expression Gene Expression Regulation Genetic Transcription Goals Grant Hemochromatosis Homeostasis Investigation Ions Iron Iron Regulatory Protein 1 Iron-Regulatory Proteins Laboratories Link Lipids Malignant Neoplasms Mediating Mediator of activation protein Messenger RNA Metabolic Pathway Metabolism Modeling Molecular N-terminal NCOA4 gene Nucleotides Oxidative Stress Pathogenesis Pathway interactions Phosphotransferases Physiological Play Proline Proteins Proteomics RNA-Binding Proteins Regulation Research Role Signal Pathway Signal Transduction System Testing Toxic effect Trace metal Ubiquitin Work base design insight iron deficiency iron metabolism mRNA Expression multicatalytic endopeptidase complex novel prevent protein complex protein expression public health relevance response ubiquitin ligase ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Intracellular iron homeostasis is a critical cellular process that ensures intracellular iron concentrations are sufficient to perform essential iron-dependent functions in aerobic respiration, DNA replication and repair, and multiple biosynthetic pathways (amino acid, nucleotide, and lipid) while avoiding the toxicity associated with excess iron. We previously identified the E3 ubiquitin ligase FBXL5 as a master regulator of iron homeostasis that was responsible for "sensing" intracellular iron levels through an N-terminal iron-binding domain and coupling changes in iron concentration to its ability to degrade Iron Regulatory Proteins (IRPs) - RNA binding proteins that the post-transcriptional expression of genes involved iron utilization, transport, and storage. In the proposed work, we will examine the hypothesis that FBLX5 is a key signaling hub that coordinates IRP- mediated gene regulation with variety of other iron metabolic pathways in order to generate an integrated cellular response to iron deficiency. Specific aim 1 will explore the role of the Fe-S cluster assembly pathways in regulating iron homeostasis by characterizing a novel interaction identified in our laboratory between FBXL5 and the CIA targeting complex, a protein complex required for Fe-S protein biogenesis. In specific aim 2, we will elucidate the cellular mechanism by which FBXL5 is degraded in iron-depleted cells by defining the roles of the E3 ubiquitin ligase HERC2 and the kinase SPAK in this proteolytic pathway. Finally, specific aim 3 will focus on examining a role for FBXL5 in regulating ferritin degradation via its association with the autophagy adaptor NCOA4. Investigation of these three aims will uncover the molecular mechanisms that govern how FBXL5 integrates and interprets signals transduced through multiple iron-regulated signaling pathways in order to dictate the multi-faceted cellular response to iron availability.

描述（由申请人提供）：细胞内铁稳态是一个关键的细胞过程，可确保细胞内铁浓度足以执行有氧呼吸、DNA 复制和修复以及多种生物合成途径（氨基酸、核苷酸和脂质）中必需的铁依赖性功能。），同时避免与过量铁相关的毒性。我们之前发现 E3 泛素连接酶 FBXL5 是负责“感知”的铁稳态的主要调节因子。通过 N 端铁结合结构域调节细胞内铁水平，并将铁浓度的变化与其降解铁调节蛋白 (IRP) 的能力耦合起来。IRP 是一种 RNA 结合蛋白，涉及铁利用、运输和储存的基因的转录后表达。在拟议的工作中，我们将检验这样的假设：FBLX5 是一个关键的信号传导中枢，它协调 IRP 介导的基因调控与各种其他铁代谢途径，以产生针对缺铁的综合细胞反应。具体目标 1 将探讨其作用。的Fe-S 簇途径组装通过表征我们实验室中发现的 FBXL5 和 CIA 靶向复合物（Fe-S 蛋白生物发生所需的蛋白质复合物）之间的新型相互作用来调节铁稳态。在具体目标 2 中，我们将通过以下方式阐明细胞机制。通过定义 E3 泛素连接酶 HERC2 和激酶 SPAK 在该蛋白水解途径中的作用，FBXL5 在铁耗尽的细胞中被降解。最后，具体目标 3 将重点关注。审查一个角色 FBXL5 通过与自噬接头 NCOA4 的关联来调节铁蛋白降解，对这三个目标的研究将揭示控制 FBXL5 如何整合和解释通过多个铁调节信号通路转导的信号的分子机制，以决定多方面的细胞反应。铁的可用性。