The cellular filopodia mechanism in Shigella membrane protrusion formation

志贺氏菌膜突起形成的细胞丝状伪足机制

基本信息

批准号：
8430385
负责人：
Marcia B Goldberg
金额：
$ 26.1万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8430385
关键词：
Actins Bacteria Cell Surface Extensions Cell membrane Cell physiology Cells Cellular Membrane Cessation of life Colorectal Complex Cytolysis Cytoskeleton Data Diarrhea Disease Dysentery Endocytosis Enteral Environment Epithelial Cells Epithelium Escherichia coli EHEC Family Filament Filopodia Generations Gray unit of radiation dose Homologous Gene Human Human Cell Line Infection Insulin Receptor Intestines Investigation Lead Link Membrane Molecular Movement Neoplasm Metastasis Organism Pathogenesis Pathway interactions Phosphorylation Phosphotransferases Plasma Play Process Proteins Recruitment Activity Role Shapes Shigella Shigella flexneri Signaling Molecule Signaling Protein Source Tail Tertiary Protein Structure Testing Tissues Vacuole amphiphysin base cell motility design dimer human tissue improved insight intestinal epithelium link protein member monolayer pathogen polymerization public health relevance uptake vasodilator-stimulated phosphoprotein

项目摘要

DESCRIPTION (provided by applicant): Shigella are intracellular enteric human pathogens that move to the cell periphery via actin-based motility, whereupon they generate protrusions of the plasma membrane that penetrate into and are taken up by adjacent uninfected cells. The generation of plasma membrane protrusions is critical for Shigella spread, but the mechanisms involved are poorly understood. We have shown that cellular diaphanous formins and IRTKS are each required for both efficient formation of plasma membrane protrusions and efficient spread of Shigella through cell monolayers. Both diaphanous formins and the IRTKS homolog IRSp53 are components of the cellular fiolopodia tip complex and both are required for efficient formation of filopodia. IRTKS and IRSp53 are I-BAR domain proteins that link the plasma membrane with the cytoskeleton while inducing concave deformations of the membrane. Based on these results, we hypothesize that Shigella generation of plasma membrane protrusions utilizes the cellular filopodia formation machinery. In this application, we propose a set of exploratory investigations to test our hypothesis. Our specific aims are as follows: Aim 1. Analysis of IRTKS functions involved in Shigella protrusion formation. Aim 2. Test the role of Tyr phosphorylation of IRTKS in S. flexneri protrusion formation. Aim 3. Determine whether other interactors of I-BAR domain proteins are required for efficient generation of plasma membrane protrusions by S. flexneri. The investigations proposed in this application are highly likely to generate new insights into the mechanisms of Shigella spread through the intestinal epithelium, as well as into the fundamental processes involved in cellular membrane protrusion, particularly filopodia formation.

描述（由申请人提供）：志贺氏菌是细胞内的肠内病原体，通过基于肌动蛋白的运动转移到细胞周围，因此它们会产生质膜的突起，这些质膜渗透到相邻的未感染细胞中并将其吸收。质膜突起的产生对于志贺氏菌扩散至关重要，但是所涉及的机制知之甚少。我们已经表明，细胞拟透明的造型和IRTK既需要有效地形成质膜突起，又需要Shigella通过细胞单层的有效扩散。 diaphanous formins和irtks同源物IRSP53都是细胞梗死尖端复合物的组成部分，两者都是有效形成丝状菌素所必需的。 IRTK和IRSP53是I-BAR结构域蛋白，它们将质膜与细胞骨架联系起来，同时诱导膜的凹形变形。基于这些结果，我们假设志贺氏菌的生成质膜突起利用细胞丝状形成机械。在此应用程序中，我们提出了一组探索性研究以检验我们的假设。我们的具体目的如下：目标1。对志贺氏菌突出形成的IRTKS功能的分析。 AIM 2。测试IRTKS在屈曲链球菌突出形成中的Tyr磷酸化的作用。 AIM 3。确定是否需要S. flexneri有效地产生质膜突起的I-BAR结构域蛋白的其他相互作用。本申请中提出的调查很可能会产生对该应用的新见解志贺氏菌的机制通过肠上皮以及涉及细胞膜突起的基本过程，尤其是丝状形成。