The role of NCOA4-mediated ferritinophagy in iron homeostasis and ferroptosis
NCOA4介导的铁蛋白自噬在铁稳态和铁死亡中的作用
基本信息
- 批准号:10370294
- 负责人:
- 金额:$ 36.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAffectAutophagocytosisAutophagosomeBindingBiochemicalBiologicalBiological ModelsCRISPR/Cas technologyCell Culture SystemCell Culture TechniquesCell DeathCell NucleusCell modelCellsChelating AgentsComplexCytoplasmDNA RepairDNA biosynthesisDataDependenceDiseaseElementsEquilibriumErythrocytesErythropoiesisFTH1 geneFerritinFunctional disorderGenerationsHealthHemeHemochromatosisHemoglobinHomeostasisIn VitroInjury to KidneyIronIron OverloadIron deficiency anemiaIron-Regulatory ProteinsKnock-outLifeLightLinkLipid PeroxidationLysosomesMalignant NeoplasmsMass Spectrum AnalysisMediatingMineralsMitochondriaModelingMolecularMusNCOA4 geneNuclear Receptor Coactivator 4OxygenPancreatic Ductal AdenocarcinomaPathologicPathway interactionsPhysiologicalPhysiological ProcessesPhysiologyProcessProductionProteomicsReactive Oxygen SpeciesRegulationReperfusion InjuryReportingRoleTherapeuticTimeTissuesWorkZebrafishbasedeprivationferrihydritegenome editinghuman diseaseimprovedin vivoinsightiron deficiencyiron metabolismliver injurymicrocytic/hypochromic anemiamouse modelmutantnoveloverexpressionprotein complexproteostasisreceptorresponsetherapeutic targettooltraffickingubiquitin-protein ligase
项目摘要
The role of NCOA4-mediated ferritinophagy in iron homeostasis and ferroptosis Iron is essential for nearly all forms of life given the requirement for iron in oxygen binding and transport, ATP production, and DNA replication and repair. Cells must maintain sufficient iron levels to support these processes; however, iron excess can be detrimental given the role of iron in generation of toxic reactive oxygen species. To achieve this balance, cellular iron is primarily stored in a non-toxic form in ferritin, a protein complex composed of 24 subunits of ferritin light and heavy chain subunits. However, the mechanism of iron release from ferritin in times of cellular demand was unclear until recently. We identified NCOA4 as the selective cargo receptor that mediates the autophagic degradation of ferritin (“ferritinophagy”) thereby releasing iron for use by the cell. Flux through the ferritinophagy pathway is dependent on NCOA4 protein levels which are regulated by intracellular iron levels. Under iron-replete cellular conditions, NCOA4 binding to HERC2, an E3 ubiquitin ligase, is increased, leading to proteasomal degradation of NCOA4. Decreased NCOA4 levels inhibit ferritinophagy thereby increasing ferritin iron storage. Under iron-deficient conditions, HERC2 binding to NCOA4 is decreased, leading to NCOA4 stabilization and induction of ferritinophagy for iron release. Ferritinophagy is involved in iron- dependent physiological processes such as erythropoiesis, where NCOA4 mediates ferritin iron release for mitochondrial heme synthesis. Recently, in cell culture models, ferritinophagy has been shown to regulate ferroptosis, a newly described form of iron-dependent cell death mediated by excess lipid peroxidation. Dysregulation of iron metabolism and ferroptosis have been described in hemochromatosis and acute ischemic kidney injury; however, little is known about the in vivo role of ferritinophagy in regulating sensitivity to ferroptosis. In the proposed work, we will examine the hypothesis that NCOA4 is a key regulator of cellular and systemic iron homeostasis with specific temporal and spatial roles in regulating iron homeostasis in physiology and pathophysiology. Specific Aim 1 will define the biochemical mechanisms regulating NCOA4 activity in cells using an integrated quantitative proteomic and cell biologic experimentation workflow. In specific aim 2, we will determine the temporal and spatial dependency of ferritinophagy in vivo for regulating systemic iron homeostasis and erythropoiesis using novel mouse models of NCOA4 knockout and over-expression. Finally, specific aim 3 will focus on examining a role for NCOA4 in regulating sensitivity to ferroptosis in vivo under pathophysiologic conditions. Together, the proposed in vitro and in vivo studies will identify fundamental roles of NCOA4 in sensing and responding to iron deficiency and overload and determine the utility of pursuing NCOA4 as a therapeutic target for multiple iron-related disorders.
NCOA 4介导的铁蛋白吞噬在铁稳态和铁凋亡中的作用铁对于几乎所有形式的生命都是必需的,因为在氧结合和运输、ATP产生以及DNA复制和修复中需要铁。细胞必须保持足够的铁水平来支持这些过程;然而,铁过量可能是有害的,因为铁在产生有毒的活性氧中起作用。为了实现这种平衡,细胞铁主要以无毒形式储存在铁蛋白中,铁蛋白是由铁蛋白轻链和重链亚基的24个亚基组成的蛋白质复合物。然而,直到最近,铁蛋白在细胞需求时释放铁的机制还不清楚。我们将NC 0A 4鉴定为介导铁蛋白的自噬降解(“铁蛋白吞噬”)从而释放铁供细胞使用的选择性货物受体。通过铁蛋白吞噬途径的通量依赖于由细胞内铁水平调节的NCOA 4蛋白水平。在充满铁的细胞条件下,NCOA 4与HERC 2(一种E3泛素连接酶)的结合增加,导致NCOA 4的蛋白酶体降解。降低的NCOA 4水平抑制铁蛋白吞噬,从而增加铁蛋白铁储存。在缺铁条件下,HERC 2与NCOA 4的结合减少,导致NCOA 4稳定并诱导铁蛋白吞噬以释放铁。铁蛋白吞噬涉及铁依赖性生理过程,如红细胞生成,其中NC 0A 4介导铁蛋白铁释放用于线粒体血红素合成。最近,在细胞培养模型中,铁蛋白吞噬已被证明可以调节铁凋亡,这是一种新描述的由过量脂质过氧化介导的铁依赖性细胞死亡形式。在血色病和急性缺血性肾损伤中已经描述了铁代谢失调和铁凋亡;然而,关于铁蛋白吞噬在调节对铁凋亡的敏感性中的体内作用知之甚少。在拟议的工作中,我们将研究的假设,NCOA 4是一个关键的调节细胞和全身铁稳态与特定的时间和空间的作用,在调节铁稳态的生理和病理生理。具体目标1将使用集成的定量蛋白质组学和细胞生物学实验工作流程来定义调节细胞中NCOA 4活性的生化机制。在具体目标2中,我们将使用NCOA 4敲除和过表达的新型小鼠模型确定体内铁蛋白吞噬的时间和空间依赖性,以调节全身铁稳态和红细胞生成。最后,具体目标3将集中于检查NCOA 4在病理生理条件下体内调节对铁凋亡的敏感性的作用。总之,拟议的体外和体内研究将确定NCOA 4在感知和响应铁缺乏和过载中的基本作用,并确定将NCOA 4作为多种铁相关疾病的治疗靶点的效用。
项目成果
期刊论文数量(0)
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Joseph D Mancias其他文献
<em>In Vivo</em> barcoded CRISPR-Cas9 Screen Identifies <em>Ncoa4-</em>mediated Ferritinophagy As a Dependence in <em>Tet2</em>-Deficient Haemopoiesis
- DOI:
10.1182/blood-2024-200955 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Justin CT Loke;Geon Geon Kim;Meaghan Boileau;Thuy T.P. Nguyen;Marie E McConkey;Aidan P. Miller;Wesley Shin;Christopher B. Hergott;Maria Ericsson;Anja E.H. Nordstrom;Scott A Armstrong;Joseph D Mancias;Benjamin Levine Ebert - 通讯作者:
Benjamin Levine Ebert
emIn Vivo/em barcoded CRISPR-Cas9 Screen Identifies emNcoa4-/emmediated Ferritinophagy As a Dependence in emTet2/em-Deficient Haemopoiesis
体内条形码CRISPR - Cas9筛选确定Ncoa4介导的铁蛋白自噬是Tet2缺陷型造血过程中的一种依赖性
- DOI:
10.1182/blood-2024-200955 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:23.100
- 作者:
Justin CT Loke;Geon Geon Kim;Meaghan Boileau;Thuy T.P. Nguyen;Marie E McConkey;Aidan P. Miller;Wesley Shin;Christopher B. Hergott;Maria Ericsson;Anja E.H. Nordstrom;Scott A Armstrong;Joseph D Mancias;Benjamin Levine Ebert - 通讯作者:
Benjamin Levine Ebert
Joseph D Mancias的其他文献
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{{ truncateString('Joseph D Mancias', 18)}}的其他基金
The role of NCOA4-mediated ferritinophagy in iron homeostasis and ferroptosis
NCOA4介导的铁蛋白自噬在铁稳态和铁死亡中的作用
- 批准号:
10597588 - 财政年份:2020
- 资助金额:
$ 36.76万 - 项目类别:
Cargo selectivity of the mammalian COPII coat complex
哺乳动物 COPII 外套复合物的货物选择性
- 批准号:
7492404 - 财政年份:2004
- 资助金额:
$ 36.76万 - 项目类别:
Cargo selectivity of the mammalian COPII coat complex
哺乳动物 COPII 外套复合物的货物选择性
- 批准号:
6951858 - 财政年份:2004
- 资助金额:
$ 36.76万 - 项目类别:
Cargo selectivity of the mammalian COPII coat complex
哺乳动物 COPII 外套复合物的货物选择性
- 批准号:
7123783 - 财政年份:2004
- 资助金额:
$ 36.76万 - 项目类别:
Cargo selectivity of the mammalian COPII coat complex
哺乳动物 COPII 外套复合物的货物选择性
- 批准号:
6893193 - 财政年份:2004
- 资助金额:
$ 36.76万 - 项目类别:
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