The role of the ZNG1 metallochaperone in the host response to infection

ZNG1 金属伴侣在宿主感染反应中的作用

• 批准号: 10753132
• 负责人: DAVID P. GIEDROC
• 金额: $ 56.3万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753132
• 关键词: Ablation; Affect; Animals; Binding; Biochemical; Biological; Biology; Cell physiology; Cells; Chemicals; Client; Clinical; Communicable Diseases; Complex; Cytosol; Data; Defect; Developing Countries; Development; Dietary Intervention; Dietary Zinc; Enzymes; Etiology; Exhibits; Family; Gene Expression; Genetic Transcription; Growth; Guanosine Triphosphate Phosphohydrolases; Homeostasis; Host Defense; Human; Immune response; Incidence; Infection; Life; Ligands; Link; Maintenance; Malignant Neoplasms; Mediating; Metalloproteins; Metals; Micronutrients; Modeling; Molecular; Molecular Chaperones; Mus; N-terminal; Names; Nature; Nucleotides; Outcome; Peptide Hydrolases; Persons; Physiological; Physiology; Play; Population; Predisposition; Process; Proteins; Proteome; Public Health; Regulation; Reporting; Risk Factors; Role; Single Nucleotide Polymorphism; Starvation; Structure; Testing; Therapeutic; Tissues; Transition Elements; Translation Process; ZFHX3 gene; Zebrafish; Zinc; Zinc Fingers; Zinc deficiency; cellular development; cofactor; combat; defined contribution; experimental study; human disease; immune function; in vivo; infection risk; insight; metalloenzyme; methionyl aminopeptidase; mortality; nervous system disorder; nutrition; protein function; proteostasis; response; transcription factor

SUMMARY Zinc binding metalloproteins and metalloenzymes constitute approximately 10% of the vertebrate proteome and are essential for many cellular processes. Due to the critical importance of zinc to vertebrate physiology, zinc deficiency leads to growth defects, aberrant immune function, neurological disorders, cancers, and increased risk of infection. This is a pervasive public health problem considering that approximately half of the world's population suffers from dietary zinc deficiency, now the fifth most important risk factor for mortality in developing countries. Although the clinical link between Zn deficiency and infection is established, the molecular mechanisms are not well understood. Despite the known importance of zinc cofactors to cellular function, the mechanism by which zinc is inserted into metalloproteins is poorly understood. In this application we report our discovery of zinc-regulated GTPase metalloprotein activator 1 (Zng1) as the first reported zinc metallochaperone that inserts zinc into cognate client metalloproteins. We identify the protein processing enzyme methionine aminopeptidase 1 (Metap1) and the transcription factor zinc finger homeobox 3 (Zfhx3) as Zng1 clients, and we describe a conserved domain that mediates an interaction between Zng1 and these metalloproteins. This finding forms the basis of proposed structural, biochemical, and physiological experiments to define the mechanism of Zng1-dependent metal delivery to client proteins. Single nucleotide polymorphisms in Zng1 are associated with increased incidence of severe infections in humans, establishing an important link between Zng1 and infection in the zinc starved host. Zng1-dependent metal transfer increases the functional activities of Metap1 and Zfhx3, and loss of Zng1 activity in mice and zebrafish negatively impacts organismal development and increases susceptibility to multiple infectious diseases. Based on these findings, we propose a model whereby the Zng1 family of enzymes are evolutionarily conserved metallochaperones that transfer zinc to Metap1 and Zfhx3 during conditions of extreme zinc deficiency. We predict that this process of co-factor delivery leads to regulated protein processing through Metap1 and coordinated gene expression changes through Zfhx3. Combined, these activities help orchestrate the cellular response to infection during zinc starvation. Experiments described in this proposal will test this model and determine the molecular mechanism by which Zng1 transfers metal to Metap1 and Zfhx3, define the role of Zng1-client interactions in proteostasis and transcription, and reveal the in vivo contribution of Zng1 metal delivery to vertebrate defense against infection. Collectively, findings from this proposal will uncover the biological and pathophysiological relevance of this newly identified family of zinc metallochaperones and make important contributions to nutrition and infection biology.

总结 锌结合金属蛋白和金属酶约占脊椎动物蛋白质组的10%， 对许多细胞过程至关重要。由于锌对脊椎动物生理学的至关重要性， 缺乏导致生长缺陷，异常的免疫功能，神经系统疾病，癌症，和增加 感染的风险。这是一个普遍的公共卫生问题，因为世界上大约一半的人口 膳食锌缺乏是发展中国家死亡率的第五大危险因素， 国家虽然锌缺乏症和感染之间的临床联系已经建立，但分子生物学上， 机制还不太清楚。尽管已知锌辅因子对细胞功能的重要性， 锌插入金属蛋白的机制知之甚少。在此应用程序中，我们报告我们的 发现锌调节的GT3金属蛋白激活剂1（Zng 1）作为首次报道的锌金属伴侣 将锌插入同源客户金属蛋白中。我们鉴定了蛋白质加工酶蛋氨酸 氨肽酶1（Metap 1）和转录因子锌指同源框3（Zfhx 3）作为Zng 1客户，我们 描述了介导Zng 1和这些金属蛋白之间相互作用的保守结构域。这一发现 形成了拟议的结构，生物化学和生理实验的基础，以确定 Zng 1-依赖金属传递到客户端蛋白质。Zng 1单核苷酸多态性与 人类严重感染的发生率增加，在Zng 1和感染之间建立了重要联系 在锌饥饿的宿主体内Zng 1依赖的金属转移增加了Metap 1和Zfhx 3的功能活性， 在小鼠和斑马鱼中，Zng 1活性的丧失对生物体的发育产生负面影响， 易患多种传染病。基于这些发现，我们提出了一个模型，其中Zng 1 酶家族是进化上保守的金属伴侣蛋白，其在代谢过程中将锌转移到Metap 1和Zfhx 3。 极度缺锌的情况。我们预测辅因子的传递过程会导致调节蛋白质的表达。 通过Metap 1进行加工，通过Zfhx 3进行协调基因表达变化。这些活动结合起来， 帮助协调细胞对锌饥饿期间感染的反应。本提案中描述的实验 将测试这个模型，并确定Zng 1将金属转移到Metap 1和Zfhx 3的分子机制， 定义Zng 1-客户端相互作用在蛋白质稳定和转录中的作用，并揭示Zng 1-客户端相互作用在体内的作用。 锌金属传递到脊椎动物防御感染。总的来说，这项提案的结果将揭示 新发现的锌金属伴侣蛋白家族的生物学和病理生理学相关性， 对营养学和感染生物学做出了重要贡献。