Characterization of the antiviral and nuclear regulatory functions of FEZ1 & NEK1

FEZ1 抗病毒和核调节功能的表征

基本信息

批准号：
8550105
负责人：
Mojgan Hosseini Naghavi
金额：
$ 29.34万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-24 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8550105
关键词：
Affect Antiviral Agents Architecture Binding Biological Assay Blindness Capsid Carrier Proteins Cell Nucleus Cells Co-Immunoprecipitations Complex Cornea Cytoplasm DNA DNA Viruses Data Ectopic Expression Encephalitis Escape Mutant Goals HIV-1 Herpes Labialis Herpesvirus 1 Infection Integration Host Factors Learning Location Mediating Microglia Microtubule-Organizing Center Microtubules Motor Movement Neurons Nuclear Nuclear Envelope Pattern Phenotype Play Polyomavirus Population Poxviridae Predisposition Process Property Protein Kinase Proteins Regulation Resistance Retroviridae Role Signal Pathway Signal Transduction Testing Therapeutic Intervention Travel Vaccinia virus Viral Viral Proteins Virus Virus Diseases Work Yeasts acquired immunodeficiency brain cell cell type inhibitor/antagonist insight member neurotropic neurotropic virus nucleocytoplasmic transport overexpression particle protein complex trafficking viral DNA yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Human immunodeficiency virus type 1 (HIV-1) is a member of the retroviridae that causes Acquired Immunodeficiency Syndome (AIDS), which affects over 33.3 million people worldwide. Like many viruses, retroviruses require access to the host nucleus in order to replicate yet the processes and factors involved remain poorly understood. After entry into the cell, viral particles transit the cytoplasm to the nucleus on host microtubules, long filamentous transport networks that arrange around the microtubule organizing centre (MTOC) located near the nucleus. Our recent work has identified a neuronal protein, FEZ1 that localizes to the MTOC and suppress infection by a number of retroviruses, including HIV-1, by blocking the entry of viral DNA into the nucleus. Our preliminary data also suggests that the FEZ1 interacting protein, NEK1 has a similar neuronal expression pattern and inhibitory effect on HIV-1 infection, suggesting that FEZ1 and at least some of its interacting proteins may form part of a neuronal complex that impairs retroviral infection. Our additional preliminary data shows that FEZ1 also suppresses infection by another clinically important neurotropic DNA virus, Herpes Simplex Virus type 1 (HSV-1), suggesting that FEZ1 expression in neurons may limit their susceptibility to infection by a number of distinct viruses. Finally, ectopic expression of FEZ1 in microglia, another brain cell type, causes changes in nuclear architecture, called multi-lobulation, which may contribute to its antiviral properties and which suggests that FEZ1 and its interacting proteins may regulate important, poorly understood functions of the nucleus itself. In this proposal, we aim to characterize the antiviral and nuclear regulatory functions of FEZ1 in detail, defining the domains involved in regulating infection as well as those involved in the formation of multi-lobulated nuclei, and determining the regulation of FEZ1 function by host signaling pathways. By also examining the contribution of additional FEZ1- and NEK1-interacting factors to the phenotypes observed, we hope to build a picture of how these proteins regulate viral infection and nuclear architecture or movement, which will provide important insights into how factors associated with the MTOC communicate with and regulate nuclear functions important for viral infection and the broader movement of large cargoes, such as viral capsids, into the nucleus. As such, these studies are also likely to contribute to our broader understanding of the control of nuclear transport and architecture.

描述（由申请人提供）：人类免疫缺陷病毒1型（HIV-1）是逆转录病毒科的成员，导致可获得的免疫缺陷集团（AIDS），影响了全球超过3330万人。像许多病毒一样，逆转录病毒需要进入宿主核以复制宿主核，但所涉及的过程和因素仍然了解不足。进入细胞后，病毒颗粒将细胞质转移到宿主的核微管，长丝状运输网络，它们在核附近的微管组织中心（MTOC）周围排列。我们最近的工作已经确定了一种神经元蛋白FEZ1，该蛋白将其定位在MTOC中，并通过阻断病毒DNA进入细胞核的许多逆转录病毒（包括HIV-1）抑制感染。我们的初步数据还表明，FEZ1相互作用的NEK1具有相似的神经元表达模式和对HIV-1感染的抑制作用，这表明FEZ1及其至少某些相互作用的蛋白可能构成神经元复合物的一部分，以促进逆转录病毒感染。我们的其他初步数据表明，FEZ1还抑制了另一种临床上重要的神经性DNA病毒的感染，即单纯疱疹病毒1型（HSV-1），这表明神经元中的Fez1表达可能会限制其对感染的易感性，以通过许多不同病毒。最后，Fez1在小胶质细胞（另一种脑细胞类型）中的异位表达会导致核结构的变化，称为多细胞化，这可能有助于其抗病毒特性，这表明FEZ1及其相互作用的蛋白质可能调节重要的，核心本身的功能不足。在此提案中，我们旨在表征抗病毒和核 FEZ1的调节函数详细定义了与调节感染有关的域以及与形成多裂料核形成的域，并通过宿主信号通路确定FEZ1功能的调节。 By also examining the contribution of additional FEZ1- and NEK1-interacting factors to the phenotypes observed, we hope to build a picture of how these proteins regulate viral infection and nuclear architecture or movement, which will provide important insights into how factors associated with the MTOC communicate with and regulate nuclear functions important for viral infection and the broader movement of large cargoes, such as viral capsids, into the nucleus.因此，这些研究也可能有助于我们对核运输和建筑的控制更广泛地理解。