Role of Ifitm/Fragilis proteins as intracellular shuttles during cell activation

Ifitm/Fragilis 蛋白在细胞激活过程中作为细胞内穿梭机的作用

基本信息

批准号：
8197848
负责人：
John Weis
金额：
$ 18.69万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197848
关键词：
Adhesions Animals Autoimmunity B-Lymphocytes Binding Biological Biological Assay CD81 gene Cell Proliferation Cell Surface Receptors Cell membrane Cell physiology Cell surface Cells Cellular Membrane Complex Cytoplasm Depressed mood Down-Regulation Enzymes Event Family member Future Goals Human Immune Immune response Infection Interferon Activation Interferon Type II Interferons Lead Location Mammalian Cell Membrane Membrane Microdomains Membrane Proteins Modeling Modification Molecular Movement Mus Normal Cell Pathway interactions Phagocytes Phenocopy Phenotype Post-Translational Protein Processing Production Property Protein Binding Protein Kinase Proteins Publications Rest Role Set protein Signal Transduction Site Surface Testing Tissues Ubiquitin Viral Virus Virus Diseases Yeasts base design human PHEMX protein macrophage man migration prevent protein degradation protein function public health relevance receptor research study response restoration yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): The central focus of this project is to test the hypothesis that the Ifitm proteins down-modulate cell activation and prevent viral infections by shuttling modifying enzymes to the cell surface to degrade activation complexes. The activation of cells of the immune response often requires signaling through cell surface receptors. This event brings into activation domains, such as lipid rafts, both the activating proteins (kinases, etc) and the substrates (receptors and intracellular signaling partners). In some cells (phagocytic cells such as macrophages and B cells) many such complexes are internalized and degraded. Other activation complexes on these and other cells, however, remain on the cell surface and require modification to block further cellular activation. The Ifitm proteins have been characterized as functioning to help down-regulate activated cells, depressing adhesion and proliferation. In addition they were recently characterized as the major determinants of the anti-viral state in mammalian cells after activation with type I and type II interferons. However, the mechanism by which the Ifitm proteins accomplish these effects has not been described. We have found that the Ifitm proteins can bind to a variety of proteins whose functions are associated with the modification of proteins by the addition of substrates (such as ubiquitin or SUMO) or enzymatic cleavage. We propose that the Ifitm proteins are held within the cell and are released following activation to intercalate within the membrane. As the Ifitm proteins make this migration, they carry these modifying proteins as cargo for association with proteins within the membrane. The delivery of these cargo proteins into activation complexes is followed by their action to degrade and/or modify surface proteins thus depressing cell activation. This same pathway is also proposed to function to control viral infection. We propose to target one specific cargo protein in particular, Bat5, which has been shown to bind to the Ifitm proteins of man and mouse. We further propose that the absence of this pathway will allow for uninhibited cellular activation potentially leading to increased cell proliferation and lack of immune control that could lead to autoimmunity and tissue damage. PUBLIC HEALTH RELEVANCE: The control of cell activation requires pathways that down regulate activating complexes and components. The Ifitm proteins have been implicated as helping depress cell activation and enhance innate immune defenses to certain viral infections but no mechanisms as to how they accomplish this have been demonstrated. We propose to test the hypothesis that the Ifitm proteins shuttle cargo enzymes into membrane activation complexes. These enzymes then target constituents of such sites for modification and degradation thus depressing activation and inhibiting infection.

描述（由申请人提供）：该项目的中心重点是测试IFITM蛋白下调细胞激活并通过将修饰酶换成细胞表面以降低活化复合物来降低病毒感染的假设。免疫反应细胞的激活通常需要通过细胞表面受体发出信号。该事件带来了激活蛋白（激酶等）和底物（受体和细胞内信号伴侣）等激活蛋白（激酶等）等激活结构域。在某些细胞中（吞噬细胞，例如巨噬细胞和B细胞），许多这样的复合物被内化和降解。但是，这些细胞和其他细胞上的其他活化复合物保留在细胞表面上，需要修饰以阻断进一步的细胞活化。 IFITM蛋白的表征是有效的，可以帮助下调活化的细胞，减轻粘附和增殖。此外，最近，它们被视为用I型和II型干扰素激活后哺乳动物细胞中抗病毒状态的主要决定因素。但是，尚未描述IFITM蛋白完成这些作用的机制。我们发现，IFITM蛋白可以通过添加底物（例如泛素或Sumo）或酶促切割而与蛋白质的修饰相关的多种蛋白质结合。我们建议将IFITM蛋白保存在细胞中，并在激活后释放以在膜内插入。由于IFITM蛋白会使这种迁移，因此它们将这些修饰的蛋白质作为货物，以与膜内蛋白关联。将这些货物蛋白递送到活化复合物中，之后是其降解和/或修饰表面蛋白的作用，从而抑制细胞活化。还提出了同样的途径来控制病毒感染。我们建议尤其是针对一种特定的货物蛋白，BAT5已显示与人和小鼠的IFITM蛋白结合。我们进一步提出，缺乏该途径将允许不抑制的细胞活化可能导致细胞增殖增加和缺乏免疫控制，从而导致自身免疫性和组织损伤。公共卫生相关性：细胞激活的控制需要降低调节激活复合物和组件的途径。 IFITM蛋白已被暗示是有助于抑制细胞激活并增强对某些病毒感染的先天免疫防御能力，但没有证明其如何完成的机制。我们建议测试IFITM蛋白途中货物中IFITM蛋白进入膜活化络合物的假设。然后，这些酶靶向此类部位的成分进行修饰和降解，从而抑制激活和抑制感染。