Proteolytic Control of Iron Metabolism by the Ubiquitin Ligase FBXL5

描述(由申请人提供)：铁是一种基本的营养物质，是许多细胞蛋白质的关键辅助因子，参与有氧呼吸、核苷酸代谢、基因表达和DNA修复。鉴于铁在维持生命中的核心作用，细胞建立了各种复杂的调节机制来控制铁的供应和使用也就不足为奇了。在描述泛素化机制在肿瘤发生中被解除调控的组件的同时，我们发现了一个名为FBXL5的泛素连接酶亚单位。在前期工作中，我们证明了FBXL5是一种新的铁代谢调节剂，它通过蛋白水解性控制铁代谢的重要效应分子的表达和细胞质中铁-硫簇的组装。这项建议的主要目标是研究FBXL5调节铁相关途径以及受铁相关途径调节的生物学机制。在特定的目标1中，我们将研究FBXL5与IRP2之间铁调节相互作用的分子基础，IRP2是铁稳态的关键调节因子。在特定目标2中的实验将围绕FBXL5本身的调节，并阐明在低铁可利用性条件下导致其蛋白酶体依赖的降解的新的蛋白分解途径。具体目标3将集中于建立FBXL5与MMS19和CIAO1之间的相互作用的功能相关性，CIAO1是线粒体外蛋白质中组装Fe/S簇所必需的胞质铁组装(CIA)途径的两个假定成分。对这三个目标的研究将提供一个全面的视角，了解FBXL5如何能够影响多个铁相关的过程。最终，我们希望这项工作将为FBXL5及其下游通路的放松管制如何促进肿瘤发生提供洞察力，同时强调潜在的新治疗策略。 公共卫生相关性：泛素与蛋白质的结合是细胞通讯的重要信号，据信在包括癌症、神经退行性疾病(如亨廷顿氏病和糖尿病)在内的多种疾病中都会受到干扰。这项建议的重点是了解细胞如何使用这种标记系统来调节铁的水平和使用。

DESCRIPTION (provided by applicant): Iron is an essential nutrient that functions as a key co-factor for many cellular proteins involved in aerobic respiration, nucleotide metabolism, gene expression, and DNA repair. Given its central role in sustaining life, it is not surprising that cells have established a variety of elaborate regulatory mechanisms to control iron availability and usage. While characterizing components of the ubiquitination machinery that are deregulated in tumorigenesis, we identified a ubiquitin ligase subunit called FBXL5. In preliminary work, we demonstrated the FBXL5 is a novel regulator of iron metabolism that proteolytically controls the expression of important effectors of iron metabolism and cytoplasmic iron-sulfur cluster assembly. The major goal of this proposal is to examine the biological mechanisms by which FBXL5 regulates and is regulated by iron-related pathways. In specific aim 1, we will examine the molecular basis of the iron-regulated interaction of FBXL5 with IRP2, a key regulator of iron homeostasis. The experiments in specific aim 2 will revolve around the regulation of FBXL5 itself and elucidating the novel proteolytic pathway responsible for its proteasome-dependent degradation under conditions of low iron availability. Specific aim 3 will focus on the establishing the functional relevance of the interaction between FBXL5 and MMS19 and CIAO1, two putative components of the cytosolic iron assembly (CIA) pathway which is required for the assembly of Fe/S clusters in extramitochondrial proteins. Investigation of these three aims will provide a comprehensive view of how FBXL5 is able to influence multiple iron-associated processes. Ultimately, we hope that this work will offer insight into how the deregulation of FBXL5 and its downstream pathways may contribute to tumorigenesis while simultaneously highlighting potential new therapeutic strategies. PUBLIC HEALTH RELEVANCE: The attachment of the ubiquitin to proteins is an important signal for cellular communication and is believed to be disrupted in multiple diseases including cancer, neurodegenerative diseases such as Huntington's disease, and diabetes. This proposal is focused on understanding how cells use this tagging system to regulate iron levels and usage.