Mechanisms of Action of Novel HIV Rev Co-factors

新型 HIV Rev 辅助因子的作用机制

• 批准号: 8843222
• 负责人: Andrew P Rice
• 金额: $ 23.68万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-01 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843222
• 关键词: Back; Binding; Biological Process; Cell Nucleolus; Cell Nucleus; Cell membrane; Cells; Cleaved cell; Complex; Cytomegalovirus; Cytoplasm; Databases; Elements; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Human; Hydrolysis; Infection; Lead; Life; Life Cycle Stages; Link; Mediating; Messenger RNA; Mining; Mouse Mammary Tumor Virus; Names; Nuclear; Nuclear Export; Nuclear Pore; Nuclear Protein; Nuclear Structure; Pathway interactions; Peptide Hydrolases; Plasmids; Process; Proteins; RNA; RNA Polymerase II; RNA Recognition Motif; RNA Splicing; Reporter; Research; Research Personnel; Research Project Grants; Response Elements; Retroviridae; Role; Signal Transduction; Small Interfering RNA; Testing; Viral; Virion; Work; cellular imaging; env Gene Products; exportin 1 protein; gp160; human disease; inhibitor/antagonist; innovation; insight; leptomycin B; novel; novel therapeutics; public health relevance; research study; rev Protein; trafficking; trans-Golgi Network; viral RNA

DESCRIPTION (provided by applicant): The HIV Rev protein is essential for viral replication and it functions to export unspliced viral RNA from the nucleus to the cytoplasm. A key cellular co-factor for Rev is the CRM1 protein (also named XPO1). The mining of a database of human nuclear protein complexes led to the identification of two proteins that associate with CRM1-- RBM14 and PACS1. SiRNA depletions experiments revealed that both RBM14 and PACS1 are required for Rev activation of two different Rev-reporter plasmids, but not for reporter plasmids dependent upon the Constitutive Transport Element (CTE) or MMTV Rev RNA export pathways. Depletion of either protein reduces the level of unspliced viral RNA in the cytoplasm, but leads to an increase in unspliced viral RNA in the nucleus. The proposed research will investigate the mechanistic roles of RBM14 and PACS1 in Rev function. This research will provide mechanistic insight into HIV Rev function, and this may provide information leading to novel therapeutic strategies for HIV infection. Additionally, the proposed work is likely to shed insight into genera mechanisms of RNA export and this may have relevance to other human diseases.

描述（由申请方提供）：HIV Rev蛋白是病毒复制所必需的，其功能是将未剪接的病毒RNA从细胞核输出到细胞质。Rev的一个关键细胞辅因子是CRM 1蛋白（也称为XPO 1）。通过对人类核蛋白复合物数据库的挖掘，发现了两种与CRM 1相关的蛋白质--RBM 14和PACS 1。SiRNA耗竭实验表明，RBM 14和PACS 1都是Rev激活两种不同Rev报告质粒所必需的，但不是依赖于组成型转运元件（CTE）或MMTV Rev RNA输出途径的报告质粒所必需的。任何一种蛋白质的缺失都会降低细胞质中未剪接的病毒RNA的水平，但会导致细胞核中未剪接的病毒RNA的增加。该研究将探讨RBM 14和PACS 1在Rev功能中的机制作用。这项研究将提供对HIV Rev功能的机制性见解，这可能为HIV感染的新治疗策略提供信息。此外，拟议的工作可能会深入了解RNA输出的一般机制，这可能与其他人类疾病有关。