Molecular functions of human zinc transporter-8 in pancreatic beta cells

人锌转运蛋白 8 在胰腺 β 细胞中的分子功能

基本信息

批准号：
10321946
负责人：
Dax Fu
金额：
$ 49.76万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321946
关键词：
Address Autoantigens Beta Cell Binding Binding Proteins Biochemistry Biological Biological Models Biology Biomimetics Carrier Proteins Cell physiology Cell surface Cells Cellular Stress Cellular biology Client Complex Coupling Crystallization Cytoplasm Data Disease Endocrine Endoplasmic Reticulum Ensure Equilibrium Exocytosis Glucose Goals Homeostasis Homologous Gene Housekeeping Human Human body Immunoassay Individual Inflammation Inflammatory Insulin Islets of Langerhans Knowledge Lipids Location Mammalian Cell Mediating Messenger RNA Metabolic Metals Minor Modeling Molecular Monoclonal Antibodies Non-Insulin-Dependent Diabetes Mellitus Pathogenesis Play Population Process Production Protein Conformation Protein Dynamics Proteins Proteome Proteomics Publishing Quality Control Regulation Research Role Secretory Vesicles Signal Transduction Specificity Stimulus Stress Structure of beta Cell of islet Surface Testing Time Tube Ubiquitination Vacuum Zinc alpha Tubulin atomic interactions base cross reactivity cytokine endoplasmic reticulum stress genetic regulatory protein insulin secretion islet loss of function mutation response restoration spatiotemporal zinc-binding protein

项目摘要

Abstract Zinc is a ubiquitous biological metal found in about 10% of the eukaryotic proteome. The spatiotemporal zinc dynamics provides crucial cellular signaling opportunities, but also challenges intracellular zinc homeostasis with broad disease implications. Zinc transporters play a central role in regulating cellular zinc balance and subcellular zinc distributions. Current biochemistry of zinc transporters is largely based on purified proteins in test-tubes. However, the molecular functions of zinc transporters in mammalian cells are cell context dependent, vary with subcellular locations and regulated by pathophysiologic stimuli. At present, we have no knowledge of in-cell functions of endogenous zinc transporters at the molecular level. To fill in this knowledge vacuum, we will use an islet-specific zinc transporter ZnT8 and its host cells, the insulin-producing pancreatic β-cells as a mammalian model system to address two questions of the greatest importance to zinc biology: (i) how ZnT8-mediated zinc transport is compartmentalized at the correct subcellular locations to perform intended tasks, (ii) how the biosynthetic burden of ZnT8 is managed by the protein quality control network that ensures clearance of terminally damaged ZnT8 under cell stress. The second question is not directly related to zinc transport, but has a profound impact on β-cell biology with implications in pathogenesis of type-2 diabetes. Our prior studies have uncovered functional coupling of ZnT8 and insulin in two critical cellular processes, glucose-stimulated insulin secretion and inflammation-induced unfolded protein response in the endoplasmic reticulum. The proposed research will characterize subcellular locations and protein levels of endogenous ZnT8 in response to metabolic and inflammatory stress (Aim-1), identify regulators of ZnT8 subcellular functions, and elucidate their mechanism of actions (Aim-2). The proposed research will reveal unprecedented molecular details of ZnT8 subcellular functions in molecular and cellular processes that impact cell biology of host cells, leading to a new paradigm of in-cell molecular functions of zinc transporters in mammalian cells.

抽象的锌是在大约10％的真核蛋白质组中发现的无处不在的生物金属动力学提供了至关重要的细胞信号传导机会广泛的疾病含义。锌分布。然而，哺乳动物细胞中锌转运蛋白的分子功能取决于细胞情境，随之而来。亚细胞的位置，并由病理生理刺激定制。内源性锌转运蛋白在分子水平上的功能。胰岛特异性锌转运蛋白Znt8及其宿主细胞，胰岛素产生的胰腺β细胞作为哺乳动物模型系统解决了两个对锌生物学最重要的问题：（i）Znt8介导的锌如何运输在正确的亚细胞位置被压缩以执行预期的任务，（ii） Znt8的生物合成负担由蛋白质质量控制网络管理，以确保清除在细胞应力下终止损坏的Znt8。对2型糖尿病的发病机理的影响对β细胞生物学有深远的影响。在两个关键过程中，Znt8和胰岛素的未共透性功能耦合，葡萄糖刺激的胰岛素分泌和炎症诱导的内质网中展开的蛋白质反应研究将表征内源性Znt8的亚细胞位置和蛋白质水平，以响应代谢和炎症应力（AIM-1），确定Znt8亚细胞功能的调节剂，并阐明其机制动作（AIM-2）。分子和细胞过程中的功能会影响宿主细胞的细胞生物学，从而导致新的范式哺乳动物细胞中锌转运蛋白的细胞内分子功能。