THE ROLE OF HIV-1 VPU IN THE REGULATION OF CD40

HIV-1 VPU 在 CD40 调节中的作用

• 批准号: 8173207
• 负责人: ASHLEE V. MOSES
• 金额: $ 15.22万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173207
• 关键词: Affect; Antiviral Agents; Area; Binding; Biological; Cells; Computer Retrieval of Information on Scientific Projects Database; Cytokine Receptors; Down-Regulation; Funding; Goals; Grant; HIV; HIV-1; Human Herpesvirus 8; Institution; Maps; Mediating; Pathogenesis; Pathway interactions; Proteins; Proteomics; Publishing; Reagent; Regulation; Research; Research Personnel; Resources; Role; Source; TNFRSF5 gene; Ubiquitin; United States National Institutes of Health; Viral; Virion; Work; beta-Transducin Repeat-Containing Proteins; novel; vpu Protein

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of this project is to understand the role of the HIV-1 protein Vpu in HIV pathogenesis. The original aim was to understand how Vpu modulates expression of the cytokine receptor CD40. Our studies showed that Vpu's effect on CD40 was due to downstream modulation of other pathways. We thus performed proteomics to identify novel cellular proteins affected by Vpu in a beta TrCP-dependent manner, and identified BST-2 as a significant Vpu target. This was important, since BST-2, was recently identified as a host antiviral factor that restricts the release of HIV from infected cells. BST-2 was renamed tetherin and independent studies confirmed our finding that Vpu antagonizes BST-2. We thus refocused our project goals to investigate the mechanisms and biological consequences of Vpu-mediated BST-2 downregulation and have made significant progress in this regards. We found that Vpu interacts with and targets BST-2 for degradation by an endosomal/lysosomal pathway and that beta TrCP is required for degradation and have published this work. We have made additional progress in the following areas i) mapping Vpu regions necessary for overcoming BST-2 restriction of viral egress; ii) characterizing the role of ubiquitin in Vpu-mediated BST-2 degradation; iii) identifying BST-2 binding partners involved in virion tethering or acting as adapters for Vpu function. This progress has allowed us submit a new R01 application "Characterization of Vpu-medicated Degradation of BST-2". Our BST-2 reagents were also used in collaborative work to examine BST-2 antagonism by the KSHV K5 protein that is now published.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该项目的总体目标是了解 HIV-1 蛋白 Vpu 在 HIV 发病机制中的作用。最初的目的是了解 Vpu 如何调节细胞因子受体 CD40 的表达。 我们的研究表明 Vpu 对 CD40 的影响是由于其他途径的下游调节。因此，我们进行了蛋白质组学，以鉴定以 β TrCP 依赖性方式受 Vpu 影响的新型细胞蛋白，并将 BST-2 确定为重要的 Vpu 靶标。 这一点很重要，因为 BST-2 最近被确定为一种宿主抗病毒因子，可以限制受感染细胞释放 HIV。 BST-2 更名为 Tetherin，独立研究证实了我们的发现，Vpu 拮抗 BST-2。 因此，我们重新调整了项目目标，研究 Vpu 介导的 BST-2 下调的机制和生物学后果，并在这方面取得了重大进展。 我们发现 Vpu 与 BST-2 相互作用并以 BST-2 为目标，通过内体/溶酶体途径进行降解，并且降解需要 β TrCP，并发表了这项工作。 我们在以下领域取得了额外进展：i) 绘制克服 BST-2 病毒出口限制所需的 Vpu 区域； ii) 表征泛素在 Vpu 介导的 BST-2 降解中的作用； iii) 鉴定参与病毒颗粒束缚或充当 Vpu 功能适配器的 BST-2 结合伴侣。 这一进展使我们能够提交新的 R01 申请“Vpu 药物降解 BST-2 的表征”。 我们的 BST-2 试剂还用于合作研究现已发表的 KSHV K5 蛋白对 BST-2 的拮抗作用。