Proteolytic Control of Iron Metabolism by the Ubiquitin Ligase FBXL5

描述（由申请人提供）：铁是一种必需营养素，作为许多细胞蛋白的关键辅助因子，参与有氧呼吸，核苷酸代谢，基因表达和DNA修复。考虑到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可用性和使用就不足为奇了。在表征泛素化机制中在肿瘤发生中不受调节的组分时，我们确定了一个称为FBXL5的泛素连接酶亚基。在前期工作中，我们证明了FBXL5是一种新的铁代谢调节剂，通过蛋白水解控制铁代谢和细胞质铁硫簇组装的重要效应物的表达。本研究的主要目的是研究FBXL5调控铁相关通路的生物学机制。在具体目标1中，我们将研究铁调控FBXL5与IRP2相互作用的分子基础，IRP2是铁稳态的关键调节因子。具体目标2中的实验将围绕FBXL5本身的调控，并阐明在低铁可用性条件下负责其蛋白酶体依赖性降解的新型蛋白水解途径。具体目标3将侧重于建立FBXL5与MMS19和CIAO1之间相互作用的功能相关性，MMS19和CIAO1是胞质铁组装（CIA）途径的两个假定成分，这是线粒体外蛋白中铁/S簇组装所必需的。对这三个目标的研究将提供FBXL5如何能够影响多个铁相关过程的全面观点。最终，我们希望这项工作能够深入了解FBXL5及其下游通路的解除管制如何促进肿瘤发生，同时突出潜在的新治疗策略。

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.