Type III effector regulation of host GTPase signaling

宿主 GTPase 信号转导的 III 型效应器调节

• 批准号: 8503581
• 负责人: Neal Mathew Alto
• 金额: $ 35.8万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-11 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503581
• 关键词: Actins; Architecture; Bacteria; Bacterial Infections; Bacterial Toxins; Bacterial Typing; Biochemical; Biological Assay; Biology; Cell model; Cells; Cellular biology; Communicable Diseases; Complex; Cytoskeleton; Destinations; Disease Progression; Environment; Enzymes; Epithelial; Epithelial Cells; Escherichia coli; Escherichia coli EHEC; Escherichia coli Proteins; Evolution; Family; Family member; Future; Genetic; Glutamic Acid; Goals; Guanine Nucleotide Exchange Factors; Guanine Nucleotides; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Health; Human; Immune response; In Vitro; Infectious Agent; Infectious Diseases Research; Intestines; Knowledge; Laboratories; Lead; Lipids; Maps; Modeling; Molecular; Molecular Machines; Natural Immunity; Needles; Pathogenesis; Pathway interactions; Property; Proteins; Regulation; Research; Research Proposals; Roentgen Rays; Role; Salmonella; Shigella; Shigella Infections; Signal Pathway; Signal Transduction; Site; Specificity; Structure; System; Testing; Tryptophan; Type III Secretion System Pathway; Virulence; Virulence Factors; Work; improved; in vivo; insight; member; molecular recognition; novel; pathogen; protein protein interaction; research study; rho; rho GTP-Binding Proteins

DESCRIPTION (provided by applicant): The type III secretion system of Gram-negative bacterial pathogens creates one of the most direct interfaces between pathogens and their hosts. These 'needle-like' molecular machines inject bacterial effector proteins directly into host cells for the purpose of destroying an innate immune response and facilitating bacterial replication, dissemination, and disease progression. Effector proteins are unique virulence factors in that they often capture or mimic the properties of host signal transduction molecules. One such target is the evolutionarily conserved Ras-superfamily of GTPases. The present study focuses on a recently identified bacterial type III effector family. The related type III effectors SifA, IpgB, and Map are required for Salmonella, Shigella, and enterohaemorrhagic E. coli pathogenesis, respectively, through their common ability to activate Rho-family GTPase signaling cascades. The studies described here seek to elucidate the host signaling mechanisms of this large bacterial virulence factor family by examining 1) the enzymatic activation of Rho GTPases, 2) type III effector recognition of GTPases at the molecular level, and 3) the effects of effector protein localization within the host cell. By revealing mechanistic details of type III effector family members, these studies will provide new insights into the pathogenic mechanisms o several infectious agents and into the biology of their human host. PUBLIC HEALTH RELEVANCE: Human Rho-family GTPases are major targets of bacterial toxins and effector proteins. Pathogens hijack this critical signaling pathway to facilitate bacterial replication, dissemination, and disease progression. This proposal examines the ability of a large family of bacterial type III effector proteins to hijack human Rho GTPases. A deeper understanding of the enzymatic and biochemical interface between these bacterial effectors and human GTPases will lead to a more complete knowledge of numerous pathogenic mechanisms and may reveal new aspects of signal transduction in the human host cell.

描述（由申请人提供）：革兰氏阴性细菌病原体的 III 型分泌系统在病原体与其宿主之间形成了最直接的界面之一。这些“针状”分子机器将细菌效应蛋白直接注入宿主细胞，目的是破坏先天免疫反应并促进细菌复制、传播和疾病进展。效应蛋白是独特的毒力因子，因为它们经常捕获或模仿宿主信号转导分子的特性。其中一个目标是进化上保守的 GTP 酶 Ras 超家族。本研究重点关注最近发现的细菌 III 型效应家族。相关的 III 型效应子 SifA、IpgB 和 Map 分别是沙门氏菌、志贺氏菌和肠出血性大肠杆菌发病机制所必需的，因为它们具有激活 Rho 家族 GTPase 信号级联的共同能力。本文描述的研究旨在通过检查 1) Rho GTPases 的酶促激活、2) 在分子水平上 GTPases 的 III 型效应器识别以及 3) 宿主细胞内效应蛋白定位的影响来阐明这一大型细菌毒力因子家族的宿主信号传导机制。通过揭示 III 型效应器家族成员的机制细节，这些研究将为了解几种感染因子的致病机制及其人类宿主的生物学提供新的见解。公共卫生相关性：人类 Rho 家族 GTP 酶是细菌毒素和效应蛋白的主要靶标。病原体劫持这一关键信号通路以促进细菌复制、传播和疾病进展。该提案检验了一大类细菌 III 型效应蛋白劫持人类 Rho GTP 酶的能力。对这些细菌效应子和人类 GTP 酶之间的酶促和生化界面的更深入了解将导致对众多致病机制的更全面的了解，并可能揭示人类宿主细胞中信号转导的新方面。