Modulation of Rab7-Dependent Degradative Pathways by Novel Adenovirus Protein

新型腺病毒蛋白对 Rab7 依赖性降解途径的调节

基本信息

批准号：
8197511
负责人：
CATHLEEN R CARLIN
金额：
$ 31.54万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197511
关键词：
Acute Adenovirus Infections Adenovirus Protein Adenoviruses Ankyrin Repeat Antigen Presentation Binding Cell Polarity Cell Surface Receptors Cells Cellular biology Cholesterol Cholesterol Homeostasis Chronic Chronic Obstructive Airway Disease Complex Cytoplasm DNA Viruses Data Degradation Pathway Disease Disease model Dynein ATPase Endocytosis Endoplasmic Reticulum Endosomes Ensure Epidermal Growth Factor Receptor Equilibrium Evolution Failure Fibroblasts Foundations GTP Binding Gene Expression Gene Transduction Agent Genes Goals Grant Review Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Human Adenoviruses IL8 gene Immune response Infection Inflammatory Integral Membrane Protein Invaded Ligands Light Lipids Lung diseases Lysosomes Maintenance Mediating Membrane Protein Traffic Microtubules Modification Molecular Monomeric GTP-Binding Proteins Motor Normal Cell Nuclear Pore Complex Nuclear Translocation Nutrient Organelles Pathogenesis Pathologic Processes Pathway interactions Patients Phenotype Pneumonia Production Proliferating Protein Binding Proteins Public Health Receptor Down-Regulation Receptor Protein-Tyrosine Kinases Receptor Signaling Recruitment Activity Recycling Regulation Research Risk Factors Role Sequence Homology Signal Transduction Sorting - Cell Movement Spectrin Sterols Stress Supraoptic Vertical Ophthalmoplegia TNF gene Tail Testing Transport Vesicles Ubiquitin Viral Yeasts base cellular targeting cholesterol trafficking design disorder risk dynactin endosome membrane extracellular human disease insight late endosome loss of function mimicry nervous system disorder novel palmitoylation pathogen receptor receptor expression research study trafficking

项目摘要

Endocytosis serves many important functions ranging from acquisition of extracellular nutrients to regulation of cell surface receptor expression and signal transduction, maintenance of cell polarity, and antigen presentation. Many intracellular pathogens hijack endocytic pathways in order to invade cells, proliferate, and ensure pathogen survival. Understanding the consequences of pathogenic infection has enabled greater understanding of the endocytic trafficking machinery. Isolated pathogenic genes have also been used to curb pathological processes associated with their cellular targets in human disease models. The focus of this proposal is to understand the molecular and cellular mechanisms employed by an integral membrane protein encoded by the early region 3 of human adenoviruses called RID¿, which was originally identified because of its ability to divert constitutively recycling EGF receptors to lysosomes. We have recently discovered that RID¿ interacts with RILP and ORP1L, two known effectors for the Rab7 GTPase that governs transport from early to late endosomes and then to lysosomes. Importantly, RID¿ compensates for Rab7 loss-of-function, suggesting it modifies endosome membrane dynamics by coordinating recruitment of Rab7 effectors to compartments that would ordinarily be perceived as early sorting endosomes. To our knowledge this is the first protein encoded by a DNA virus that functions by Rab7 mimicry. Similar to other small GTPases, Rab7 acts by cycling between an active GTP- bound state and an inactive GDP-bound state. In contrast RID¿ is a non-enzymatic intrinsic membrane protein that lacks any sequence homology to Rab7, providing a remarkable example of convergent evolution. Four specific aims will test these hypotheses. 1) RID¿ controls microtubule-dependent vesicle transport by recruiting RILP and ORP1L which then activate minus end-directed dynein-dynactin motors. 2). RID¿- RILP facilitates ESCRT-II-dependent EGF receptor sorting independent of receptor tyrosine kinase or ubiquitin status. 3) RID¿-ORP1L regulates cholesterol efflux from endosomes necessary to maintain the proper lipid balance in cells. 4) RID¿ compensates for Rab7 loss-of-function during a productive adenovirus infection, and blunts adenovirus-induced inflammatory disease by interfering with a TNF¿-EGF receptor signaling cascade that regulates IL-8 production. Altogether these studies will provide novel insights to the cell biology of membrane protein trafficking, and also the molecular basis for adenovirus-induced inflammatory disease.

内吞作用具有许多重要的功能，从获得细胞外的获取调节细胞表面受体表达和信号转导的营养，维持细胞极性和抗原表现。许多细胞内病原体劫持内吞途径以侵入细胞，增殖并确保病原体生存。了解病原感染的后果已使得更大了解内吞贩运机制。孤立的致病基因具有还用于遏制与其细胞靶标相关的病理过程人类疾病模型。该提议的重点是了解分子和通过早期编码的整合膜蛋白携带的细胞机制人类腺病毒的第3区称为RID？，最初是因为它具有组成性回收EGF受体为溶酶体的能力。我们有最近发现，RID¿与RILP和ORP1L相互作用，这两个已知效果 RAB7 GTPase管理从早期到晚内体运输，然后溶酶体。重要的是，RID？弥补了RAB7的功能丧失，暗示了这一点通过协调募集RAB7生效器来修饰内体膜动力学将通常被视为早期分类内体的隔间。向我们知识这是第一种由DNA病毒编码的蛋白模仿。与其他小型GTP酶相似，Rab7通过在主动GTP之间循环起作用。绑定状态和不活跃的GDP结合状态。相反，骑行是一种非酶固有的膜蛋白缺乏与Rab7同源的任何序列同源性，提供了融合进化的显着例子。四个具体目标将测试这些假设。 1）骑行通过招募RILP来控制微管依赖的囊泡运输然后激活减去末端导向的动力蛋白 - 二奈霉素电动机的ORP1L。 2）。骑 - RILP收藏夹ESCRT-II依赖性EGF受体分选独立于受体酪氨酸激酶或泛素状态。 3）RID� -ORP1L调节从维持细胞中适当的脂质平衡所需的内体。 4）骑补偿生产性腺病毒感染期间的RAB7功能丧失，并首先通过干扰TNF�-EGF引起腺病毒诱导的炎症性疾病调节IL-8产生的受体信号级联。这些研究总共为膜蛋白运输的细胞生物学提供新颖的见解，还提供腺病毒诱导的炎症性疾病的分子基础。