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

FEZ1 抗病毒和核调节功能的表征

• 批准号: 8930337
• 负责人: Mojgan Hosseini Naghavi
• 金额: $ 3.81万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8930337
• 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

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）：1 型人类免疫缺陷病毒 (HIV-1) 是导致获得性免疫缺陷综合症 (AIDS) 的逆转录病毒科成员，该病影响全世界超过 3330 万人。与许多病毒一样，逆转录病毒需要进入宿主细胞核才能复制，但所涉及的过程和因素仍然知之甚少。病毒颗粒进入细胞后，通过细胞质进入宿主细胞核 微管，长丝状运输网络，围绕位于细胞核附近的微管组织中心（MTOC）排列。我们最近的工作发现了一种神经元蛋白 FEZ1，它定位于 MTOC，并通过阻止病毒 DNA 进入细胞核来抑制包括 HIV-1 在内的多种逆转录病毒的感染。我们的初步数据还表明，FEZ1 相互作用蛋白 NEK1 具有类似的神经元表达模式和对 HIV-1 感染的抑制作用，这表明 FEZ1 及其至少一些相互作用蛋白可能形成损害逆转录病毒感染的神经元复合体的一部分。我们的额外初步数据显示，FEZ1 还可以抑制另一种临床上重要的嗜神经性 DNA 病毒——1 型单纯疱疹病毒 (HSV-1) 的感染，这表明神经元中 FEZ1 的表达可能会限制其对多种不同病毒感染的易感性。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，称为多分叶，这可能有助于其抗病毒特性，并表明 FEZ1 及其相互作用蛋白可能调节细胞核本身的重要但知之甚少的功能。在本提案中，我们的目标是描述抗病毒和核药物的特征 详细介绍了FEZ1的调节功能，定义了参与调节感染以及参与多分叶核形成的域，并确定了宿主信号通路对FEZ1功能的调节。通过检查其他 FEZ1 和 NEK1 相互作用因子对观察到的表型的贡献，我们希望了解这些蛋白质如何调节病毒感染和核结构或运动，这将为了解与 MTOC 相关的因子如何与病毒感染和大货物（如病毒衣壳）更广泛的运动进入细胞核重要的核功能进行通信和调节提供重要见解。因此，这些研究也可能有助于我们更广泛地了解核传输和结构的控制。