Subversion of lysosomal trafficking by HHV-7 U21

HHV-7 U21 颠覆溶酶体贩运

• 批准号: 9706283
• 负责人: AMY W HUDSON
• 金额: $ 12.65万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9706283
• 关键词: Adaptive Immune System; Administrative Supplement; Affinity; Age; Binding; Biological; Biological Assay; Biological Process; CRISPR library; CRISPR/Cas technology; Cell surface; Cells; Cellular biology; Centrifugation; Client; Co-Immunoprecipitations; Complex; Comprehension; Coupled; Cytoplasmic Tail; Data; Detection; Evolution; Genetic Screening; Glycoproteins; Goals; Golgi Apparatus; Herpesviridae; Histocompatibility Antigens Class I; Host Defense Mechanism; Human Herpesvirus 6; Human Herpesvirus 7; Immune; Immune Evasion; Immune response; In Vitro; Integral Membrane Protein; Lead; Libraries; Life; Ligands; Lighting; Lysosomes; Mediating; Microscope; Microscopy; Mitochondria; Molecular; Mutate; Pathogenesis; Pathway interactions; Physiologic pulse; Play; Population; Prevention; Process; Proteins; RNA Interference; Role; Route; Signal Transduction; Sorting - Cell Movement; Structure; Textbooks; Transmembrane Domain; Viral Proteins; Virus; experimental study; genome-wide; in vivo; instrument; mutant; nanomolar; novel; protein transport; proteostasis; small hairpin RNA; success; symposium; trafficking

PROJECT SUMMARY/ABSTRACT. The goal of this administrative supplement request is to provide a state-of-the- art microscope for cell biological studies of lysosomal sorting for R01GM120735. The requested instrument will be shared equally with Drs. Blake Hill (R01GM067180.) and Matt Scaglione (R35GM119544) for their cell biological studies in mitochondria fission and proteostasis, respectively. The herpesviruses have co-evolved with their hosts for hundreds of millions of years. As our adaptive immune systems evolved, so did the mechanisms of immune evasion encoded by herpesviruses. Because herpesviruses remain latent or persistent within their host throughout life, the herpesviruses have evolved a unique set of strategies to help them contend with the lifelong host immune response. This application’s central premise is that the herpesviruses, in their evolution, have performed a 100 million-year-long genetic screen to undermine host defense mechanisms, and in so doing, can illuminate cell biological processes that we may not yet understand; we seek to take advantage of their evolution to discover new concepts in cell biology. The long term goal of this project is to understand the underlying cell biological mechanisms by which human herpesviruses-6 and -7 (HHV-6/7) escape host defense mechanisms. The focus of this proposal is to understand how HHV-7 U21 reroutes class I MHC molecules to lysosomes, and in so doing, understand the cellular pathway usurped by U21. Our preliminary data indicate that U21 employs an unknown sorting mechanism that seems to defy convention - almost certainly utilizing a novel cellular means of lysosomal sorting. In Aim 1, we assess the structure and association of U21 with itself, as a homotetramers, and determine whether homooligomerization of U21 is necessary its ability to bind to and reroute class I MHC molecules to lysosomes, and use RUSH to examine the synchronous trafficking of U21 and class I molecules to lysosomes. We ultimately seek a temporal and mechanistic view of how U21 undermines the cellular lysosomal trafficking pathway, and how this lysosomal trafficking pathway functions in the absence of U21. A better understanding of this process should contribute to our understanding of basic underlying principles of lysosomal trafficking, and also lead to a more thorough comprehension of how these viruses have such great success in evading the host immune response.

项目总结/抽象。此管理补充请求的目标是提供-的状态