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：
10544499
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/10544499
关键词：
Acute Antigen Targeting Apoptotic Autoantibodies Autoantigens Autoimmune Diabetes Automobile Driving B-Cell Antigen Receptor Beta Cell Binding Biochemistry Biology CD8-Positive T-Lymphocytes Cell physiology Cell surface Cells Chronic Client Clinical Complex Coupled Crystallization Dedications Development Diabetes Mellitus Disease Disease Progression Endocrine Endoplasmic Reticulum Environmental Risk Factor Failure Functional disorder Genes Genetic Glucose Goals Homing Human Human body Immunophenotyping Inbred NOD Mice Inflammation Inflammatory Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Knowledge Link Lipids Mediating Minor Modeling Molecular Monoclonal Antibodies Mus Non-Insulin-Dependent Diabetes Mellitus Pancreas Patients Peptides Phase Positioning Attribute Predisposition Production Protein Dynamics Proteins Publications Regulation Research Risk Role Secretory Vesicles Serum Shapes Solid Specificity Stress Structure of beta Cell of islet Surface Susceptibility Gene Therapeutic Intervention Tissues Tubulin Ubiquitination Zinc autoimmune pathogenesis autoreactive B cell blood glucose regulation cytokine cytotoxic CD8 T cells diabetes risk diabetogenic endoplasmic reticulum stress exome sequencing genome wide association study human population genetics immune cell infiltrate immunogenicity in vivo insulin secretion islet islet autoimmunity loss of function mutation molecular recognition mouse model novel therapeutic intervention protein complex protein degradation response targeted treatment type I and type II diabetes ubiquitin-protein ligase zinc-binding protein

项目摘要

The long-term goal of our research is to understand how the molecular and cellular functions of zinc transporter-8 (ZnT8) modulate pathophysiologic responses of human pancreatic beta cells to inflammatory stress and autoimmune attack. ZnT8 is a tissue-specific zinc transporter with an exceedingly high expression level in the insulin-producing beta cells that dedicate ~50% of biosynthetic capacity to insulin production and secretion upon glucose stimulation. The primary function of ZnT8 is to maintain a high zinc concentration required for proper insulin folding and crystalline packing in the insulin secretory granules, but growing evidence suggests that ZnT8 is a dynamic protein with additional functional roles on the cell surface and at the endoplasmic reticulum (ER) where ZnT8 is a major client protein of unfolded protein response leading to ZnT8 ubiquitination, immunoproteasome degradation and antigenic presentation. In addition, ZnT8 is a major cell-surface autoantigen targeted by autoreactive B cell in the earlier phase of islet autoimmunity progression to overt type-1 diabetes. The pleiotropic roles of ZnT8 shape the unique biology of beta cells and modulate their susceptibility to disease-driving inflammatory stress. Accordingly, human ZnT8 is a major self-antigen targeted for autoimmune destruction of beta cells during acute islet inflammation, and also a major ER stress burden contributing to functional failure of beta cells under chronic, low-grade inflammation. At present, it is unclear how pathophysiologic responses of human ZnT8 may increase the cell vulnerability to inflammatory stress and autoimmune attack. The proposed research will elucidate the molecular details of cytokine-induced ZnT8 ubiquitination and degradation (Aim-1), and elucidate the processing and presentation of ZnT8 autoantigen on human beta cells (Aim-2). Uncovering the molecular mechanisms driving ZnT8 targeting, degradation, and antigenic presentation will inform how ER stress and ZnT8 immunogenicity may be regulated by inflammatory stress to increase the risk of both type-1 and type-2 diabetes.

我们研究的长期目标是了解锌转运蛋白8（ZNT8）的分子和细胞功能如何调节人胰腺β细胞对炎症应激和自身免疫性攻击的病理生理反应。 Znt8是一种组织特异性的锌转运蛋白，在产生胰岛素的β细胞中具有极高的表达水平，可将生物合成能力的约50％用于葡萄糖刺激时胰岛素产生和分泌。 Znt8的主要功能是维持胰岛素分泌颗粒中适当的胰岛素折叠和结晶填料所需的高锌浓度，但是越来越多的证据表明，Znt8是一种动态蛋白，在细胞表面和在内植物表面上具有额外的功能作用降解和抗原表现。此外，Znt8是一种主要的细胞表面自身抗原，其在胰岛自身免疫性的较早阶段是由自动反应性B细胞靶向的，从而靶向明显的1型糖尿病。 Znt8的多效性作用塑造了β细胞的独特生物学，并调节其对疾病驱动炎症胁迫的敏感性。因此，人类Znt8是急性胰岛炎症期间对β细胞自身免疫性破坏的主要自我抗原，也是在慢性低级炎症下导致β细胞功能失败的主要ER压力负担。目前，尚不清楚人Znt8的病理生理反应如何增加细胞对炎症胁迫和自身免疫性攻击的脆弱性。拟议的研究将阐明细胞因子诱导的Znt8泛素化和降解（AIM-1）的分子细节，并阐明了人类β细胞上Znt8自动抗体的加工和表现（AIM-2）。揭示驱动Znt8靶向，降解和抗原呈递的分子机制将告知ER应激和ZNT8免疫原性如何受炎症应激的调节，以增加1型和2型糖尿病的风险。