Molecular interplay between T-Antigen and splicing factor, arginine/serine-rich 1 (SRSF1) controls JC virus gene expression in glial cells.
Molecular interplay between T-Antigen and splicing factor, arginine/serine-rich 1 (SRSF1) controls JC virus gene expression in glial cells.
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DOI：
10.1186/s12985-015-0426-x
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发表时间：
2015-11-24
期刊：
影响因子：
4.8
通讯作者：
Sariyer IK
中科院分区：
文献类型：
--
作者：
Craigie M;Regan P;Otalora YL;Sariyer IK
人类多瘤病毒JCV是进行性多灶性白质脑病（PML）的病因，PML是一种致命的脱髓鞘疾病，其特征是中枢神经系统胶质细胞的溶解性感染。PML主要见于免疫抑制患者，主要被归类为艾滋病定义疾病。除了结构衣壳蛋白外，JCV还编码多种调节蛋白，包括t抗原和agnoprotein，这是功能性裂解感染所必需的。先前的研究表明，病毒蛋白与宿主因子的分子相互作用在JCV的再激活和胶质细胞中病毒生命周期的进展中起着重要作用。最近，一种细胞选择性剪接因子——富丝氨酸/精氨酸剪接因子1 （SRSF1）被确定为神经胶质细胞中JCV的强负调节因子。SRSF1通过直接与病毒启动子序列相互作用抑制JCV基因表达和病毒复制。在这里，我们研究了JCV调节蛋白，t抗原和agnoprotein，对srsf1介导的胶质细胞中JCV基因表达抑制的可能影响。报告基因分析表明，t抗原可挽救SRSF1介导的病毒转录抑制。进一步的分析表明，t抗原通过抑制SRSF1基因在胶质细胞中的转录来促进病毒基因的表达。随后的ChIP分析显示，t抗原与SRSF1的启动子区域结合，诱导转录抑制。这些发现揭示了细胞SRSF1和病毒t抗原在控制JCV基因表达中的分子相互作用，并可能提示有PML风险的患者JCV再激活的新机制。
Human polyomavirus JCV is the etiologic agent of progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease characterized by lytic infection of glial cells in the central nervous system. PML is seen primarily in immunosuppressed patients and is mainly classified as an AIDS-defining disease. In addition to structural capsid proteins, JCV encodes multiple regulatory proteins, including T-antigen and agnoprotein, which are required for functional lytic infection. Previous studies have suggested that molecular interaction between viral proteins and host factors play an important role in reactivation of JCV and progression of the viral life cycle in glial cells. Recently, serine/arginine rich splicing factor 1 (SRSF1), a cellular alternative splicing factor, was identified as a strong negative regulator of JCV in glial cells. SRSF1 inhibits JCV gene expression and viral replication by directly interacting with viral promoter sequences. Here, we have investigated possible impact of JCV regulatory proteins, T-antigen and agnoprotein, on SRSF1-mediated suppression of JCV gene expression in glial cells. Reporter gene analysis has suggested that T-antigen rescues viral transcriptional suppression mediated by SRSF1. Further analyses have revealed that T-antigen promotes viral gene expression by suppressing SRSF1 gene transcription in glial cells. A subsequent ChIP analysis revealed that T-antigen associates with the promoter region of SRSF1 to induce the transcriptional suppression. These findings have revealed a molecular interplay between cellular SRSF1 and viral T-antigen in controlling JCV gene expression, and may suggest a novel mechanism of JCV reactivation in patients who are at risk of developing PML.