Regulation of erythroid iron metabolism by the CLPX unfoldase

CLPX 解折叠酶对红细胞铁代谢的调节

基本信息

批准号：
10716494
负责人：
Yvette Y Yien
金额：
$ 54.25万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-21 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10716494
关键词：
ATP phosphohydrolase ATP-Dependent Proteases Affect Allosteric Regulation Anemia Bacterial Proteins Biochemical Cell Differentiation process Cell Line Cells Cellular biology Child Complex Coupled Couples Coupling Defect Disease Enzymatic Biochemistry Enzymes Erythroid Erythroid Cells Erythropoiesis Family Functional disorder Genes Goals Health Hematological Disease Heme Heme Iron Hemoglobin Homeostasis Housekeeping Imaging Techniques Iron Iron Metabolism Disorders Iron Overload Iron-Regulatory Proteins Knowledge Label Metabolic Metabolic Pathway Metabolism Mitochondria Mitochondrial Matrix Mitochondrial Proteins Modeling Multienzyme Complexes Mutation Pathway interactions Patients Peptide Hydrolases Phenotype Play Porphyrias Porphyrins Process Production Protein Biochemistry Proteins Protoporphyrinogen oxidase Quality Control Regulation Role Severities Shapes Structure Techniques Testing Tissues Vertebrates Woman Yeasts cofactor design directed differentiation disease-causing mutation erythroid differentiation experimental study heme biosynthesis indexing innovation insight iron metabolism iron supplementation live cell imaging member metabolome multicatalytic endopeptidase complex novel polypeptide proteostasis success therapy design translational potential unfoldase uptake

项目摘要

ABSTRACT During terminal erythropoiesis, erythroid cells produce significant quantities of heme and heme intermediates which must be coupled to hemoglobin production and iron uptake. Dysregulation of heme synthesis can cause toxic accumulation of heme intermediates and heme deficiency, leading to diseases such as iron overload, anemia and porphyria. We have demonstrated that mitochondrial CLPX, a member of the ubiquitious AAA+ (ATPases associated with various cellular activities) protein unfoldases family, plays a key role in erythroid differentiation by direct regulation of heme synthesis. CLPX functions as a ring-shaped homo-hexamer and is best understood for its function in a proteasome-like enzyme complex with the peptidase CLPP (the CLPXP ATP-dependent protease). In erythroid cells, CLPX is essential for heme synthesis by regulating the terminal steps of porphyrin synthesis and mitochondrial iron metabolism. This finding is conceptually significant as ALA synthesis has until now been understood to be the rate limiting step of porphyrin synthesis. In addition, although the heme synthesis and iron metabolism pathways are coregulated, the mechanisms by which this occurs are poorly understood. This proposal tests the conceptually innovative hypothesis that CLPX coordinates the terminal steps of the heme synthesis pathway with mitochondrial iron metabolism and is a key regulatory node for coupling heme synthesis and iron metabolism to the needs of the erythroid cell. The goal of this proposal is to identify the mechanisms by which CLPX regulates erythoid heme synthesis and erythropoiesis. This will be accomplished by Specific Aim 1, which examines the novel mechanisms by which CLPX regulates the terminal enzymes of the heme synthesis pathway, PPOX and FECH. Specific Aim 2 will identify the mechanisms by which CLPX regulates mitochondrial iron metabolism and the role of iron status in modulating diseases caused by mutations in the CLPX gene. Completion of these specific aims will fundamentally inform our understanding of “housekeeping” proteins like CLPX can have tissue specific functions in erythroid cells. These findings are also of translational significance as they will enable us to determine how to manipulate iron status to treat specific types of iron/heme disorders.

抽象的在末端红细胞生成期间，红细胞细胞产生大量的血红素和血红素中间体必须将其与血红蛋白的产生和铁吸收相结合。血红素合成的失调可能导致血红素中间体和血红素缺乏症的有毒积累，导致铁超载等疾病贫血和卟啉症。我们已经证明了线粒体Clpx，ubiquiuty AAA+的成员（与各种细胞活性相关的ATPases）蛋白展开家族，在红斑中起关键作用通过直接调节血红素合成的分化。 CLPX充当环形均己，是最好理解其在蛋白酶体样酶复合物与辣椒酶CLPP中的功能（clpxp 依赖ATP的蛋白酶）。在红细胞细胞中，CLPX通过调节末端是血红素合成至关重要的卟啉合成和线粒体铁代谢的步骤。这一发现在概念上很重要，因为到目前为止，ALA合成是卟啉合成的速率限制步骤。此外，尽管血红素的合成和铁代谢途径是核心的，但该机制的机制发生的情况很差。该提案检验了CLPX的概念创新假设协调血红素合成途径的末端步骤与线粒体铁代谢，是关键用于将血红素合成和铁代谢偶联的调节节点满足了红细胞细胞的需求。目标该建议是确定CLPX调节红斑血红素合成和红细胞生成。这将通过特定的目标1来完成，该AIM 1研究了新的机制 CLPX调节血红素合成途径，PPOX和FECH的末端酶。具体目标2将确定CLPX调节线粒体铁代谢的机制以及铁状态在由CLPX基因突变引起的调节疾病。这些具体目标的完成将从根本上讲，我们对CLPX（例如CLPX）蛋白质的理解可以特定于组织在红细胞细胞中起作用。这些发现也具有转化意义，因为它们将使我们能够确定如何操纵铁状态以治疗特定类型的铁/血红素疾病。