Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2011 Jan 31;6(1):e14630. doi: 10.1371/journal.pone.0014630.
The human neurotropic virus, JC virus (JCV), is the etiologic agent of the fatal demyelinating disease of the central nervous system, Progressive Multifocal Leukoencephalopathy (PML) that is seen primarily in immunodeficient individuals. Productive infection of JCV occurs only in glial cells, and this restriction is, to a great extent, due to the activation of the viral promoter that has cell type-specific characteristics. Earlier studies led to the hypothesis that glial-specific activation of the JCV promoter is mediated through positive and negative transcription factors that control reactivation of the JCV genome under normal physiological conditions and suppress its activation in non-glial cells.
METHODOLOGY/PRINCIPAL FINDINGS: Using a variety of virological and molecular biological approaches, we demonstrate that the alternative splicing factor SF2/ASF has the capacity to exert a negative effect on transcription of the JCV promoter in glial cells through direct association with a specific DNA sequence within the viral enhancer/promoter region. Our results show that down-regulation of SF2/ASF in fetal and adult glial cells increases the level of JCV gene expression and its replication indicating that negative regulation of the JCV promoter by SF2/ASF may control reactivation of JCV replication in brain.
CONCLUSIONS/SIGNIFICANCE: Our results establish a new regulatory role for SF2/ASF in controlling gene expression at the transcriptional level.
人类亲神经病毒，JC 病毒（JCV），是一种导致中枢神经系统进行性多灶性白质脑病（PML）的致命脱髓鞘疾病的病原体，主要见于免疫功能低下的个体。JCV 的复制性感染仅发生在神经胶质细胞中，这种限制在很大程度上归因于病毒启动子的激活，该启动子具有细胞类型特异性特征。早期研究提出假设，即 JCV 启动子的神经胶质特异性激活是通过正转录因子和负转录因子介导的，这些因子在正常生理条件下控制 JCV 基因组的重新激活，并抑制其在非神经胶质细胞中的激活。
方法/主要发现：我们使用多种病毒学和分子生物学方法证明，剪接因子 SF2/ASF 能够通过与病毒增强子/启动子区域内的特定 DNA 序列直接结合，对神经胶质细胞中 JCV 启动子的转录产生负向影响。我们的结果表明，胎儿和成人神经胶质细胞中 SF2/ASF 的下调会增加 JCV 基因表达和复制水平，表明 SF2/ASF 对 JCV 启动子的负调控可能控制 JCV 复制在脑中的重新激活。
结论/意义：我们的研究结果确立了 SF2/ASF 在转录水平上控制基因表达的新调节作用。
