Neuron specific functions of HSV-1 ICP4

HSV-1 ICP4 的神经元特异性功能

• 批准号: 8277867
• 负责人: Neal A. DeLuca
• 金额: $ 22.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277867
• 关键词: Acute; Affect; Axon; Biochemical; Biology; Cell Culture Techniques; Cell Nucleus; Cells; DNA Binding Domain; Defect; Equilibrium; Exhibits; Eye; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Growth; Herpesviridae; Herpesvirus 1; Infection; Life Cycle Stages; Light; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Neuroglia; Neurons; Phenotype; Production; Proteins; Relative (related person); Repression; Simplexvirus; Specific qualifier value; Testing; Transcription Repressor/Corepressor; Viral; Viral Genes; Virion; Virus; analog; base; cell type; gene repression; in vivo; mouse model; mutant; promoter; tissue culture

DESCRIPTION (provided by applicant): ICP4 is both an activator and repressor of transcription depending on how it interacts with a viral promoter and the cellular transcription machinery. It is absolutely required for viral growth largely because it functions to activate the transcription of most viral genes to levels required for the ultimate production of progeny virions. The requirement for the repressor function of ICP4 is less well defined. While ICP4- repressible genes have been identified, the contribution of this function to the viral life cycle is not well understood. There are regions amino terminal to the DNA binding domain of ICP4 that are involved in both activation and repression of transcription and are conserved among the ICP4 analogs of 1-herpesviruses. In the context of the intact ICP4 molecule, these regions contribute little to viral growth or gene expression in tissue culture or in non-neuronal cells in vivo. However in the absence of the carboxyl-terminal activation region, mutants in the amino terminus are defective in activation and/or repression. This suggests that multiple regions of the ICP4 molecule contribute to its functions by specifying activities that may be redundant in some cell types and not others. In addition conserved regions that are not important for growth in one cell type may specify an activity that is uniquely required in another cell type. Studies from our lab suggest that there are domains of ICP4 that are required in neuronal cells and not other cell types. Studies from other labs suggest that the productive viral gene expression in neurons differs from that in non-neuronal cells. This is a very understudied aspect of HSV biology that may be crucial for our understanding of how HSV enters and reactivates from latency. The goals of this exploratory project are to identify conserved domains of ICP4 that are dispensable in cell culture, but are required for aspects of the virus life cycle in neurons or in vivo, and to begin to elucidate the molecular basis for the requirements in terms of virus gene expression and known ICP4 activities. These studies may also shed light on the basis for the different patterns of gene expression observed in neurons.

描述（由申请人提供）：ICP 4是转录的激活子和阻遏子，这取决于它如何与病毒启动子和细胞转录机制相互作用。它是病毒生长所绝对需要的，主要是因为它的功能是激活大多数病毒基因的转录，达到最终产生子代病毒体所需的水平。对ICP 4的阻遏功能的要求不太明确。虽然ICP 4抑制基因已被确定，但这种功能对病毒生命周期的贡献还不清楚。在ICP 4的DNA结合结构域的氨基末端存在区域，其参与转录的激活和抑制，并且在1-疱疹病毒的ICP 4类似物中是保守的。在完整的ICP 4分子的背景下，这些区域对组织培养物或体内非神经元细胞中的病毒生长或基因表达贡献很小。然而，在羧基末端活化区不存在的情况下，氨基末端的突变体在活化和/或抑制方面是有缺陷的。这表明ICP 4分子的多个区域通过指定在某些细胞类型中可能是冗余的而不是其他细胞类型中可能是冗余的活动来促进其功能。此外，对于一种细胞类型中的生长不重要的保守区域可以指定另一种细胞类型中唯一需要的活性。我们实验室的研究表明，ICP 4的某些结构域是神经元细胞而不是其他细胞类型所需的。其他实验室的研究表明，神经元中的生产性病毒基因表达与非神经元细胞中的不同。这是HSV生物学的一个非常未充分研究的方面，可能对我们理解HSV如何进入和从潜伏期重新激活至关重要。这个探索性项目的目标是鉴定在细胞培养中表达，但在神经元或体内病毒生命周期方面所需的ICP 4保守结构域，并开始阐明病毒基因表达和已知ICP 4活性方面要求的分子基础。这些研究也可能揭示神经元中观察到的不同基因表达模式的基础。