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，包括获取细胞外物质调节细胞表面受体表达和信号转导的营养物质，维持细胞极性和抗原呈递许多细胞内病原体。劫持内吞途径以侵入细胞、增殖并确保病原体了解病原体感染的后果可以提高生存率。对内吞运输机制的了解。也被用于抑制与其细胞靶标相关的病理过程该提案的重点是了解分子和疾病模型。早期细胞编码的整合膜蛋白所采用的细胞机制人类腺病毒的区域 3 称为 RID¿ ，最初被识别是因为我们拥有将 EGF 受体组成型再循环转移至溶酶体的能力。最近发现 RID¿与 RILP 和 ORP1L 相互作用，这两个已知的效应子 Rab7 GTPase 控制从早期内体到晚期内体的运输，然后到重要的是，RID¿补偿 Rab7 功能丧失，表明它通过协调 Rab7 效应子的募集来改变内体膜动力学通常被认为是早期分选内体的隔室。据了解，这是由 Rab7 发挥作用的 DNA 病毒编码的第一个蛋白质与其他小 GTP 酶类似，Rab7 通过在活性 GTP-之间循环发挥作用。相比之下，RID 约束状态和不活跃的 GDP 约束状态。是一种非酶促的与 Rab7 缺乏任何序列同源性的内在膜蛋白，提供了趋同进化的显着例子将检验这些目标。 1）RID¿通过募集 RILP 控制微管依赖性囊泡运输和 ORP1L，然后激活负端定向动力蛋白-动力蛋白电机 2)。 - RILP 促进 ESCRT-II 依赖性 EGF 受体分选，与受体无关酪氨酸激酶或泛素状态 3) RID¿ -ORP1L 调节胆固醇流出维持细胞内适当脂质平衡所必需的内体4) RID¿ 补偿生产性腺病毒感染期间 Rab7 的功能丧失，以及通过干扰 TNF 来减弱腺病毒诱导的炎症性疾病¿ -表皮生长因子这些研究将共同探讨调节 IL-8 产生的受体信号级联反应。为膜蛋白运输的细胞生物学提供了新的见解，并且腺病毒诱导的炎症性疾病的分子基础。