Role of Agno Protein in JC Virus Life Cycle

描述(申请人提供)：进行性多灶性白质脑病 (PML)是一种中枢神经系统(CNS)脱髓鞘疾病，由 人多瘤病毒JC对少突胶质细胞的裂解感染 病毒(PML曾被认为是中老年人的罕见并发症 淋巴增生性疾病患者。然而，近年来，越来越多的人 艾滋病患者PML的发生率高于免疫抑制患者 疾病使我们相信PML也可能被认为是与艾滋病相关的 疾病。JCV的裂解相看起来非常复杂，仍然难以捉摸。一个 越来越多的实验证据表明，对JC病毒的调控 基因的表达和复制并不是仅仅通过缺席来调节的 在特定细胞中的特定转录因子。相当精致 转录之间的相互作用或宿主与病毒之间的相互作用 调节蛋白似乎是这方面的重要决定因素。在……里面 支持这一假设，我们最近提出了具体的证据 细胞因子YB-1与JCVT抗原之间的功能相互作用 表明这两种蛋白在J的表达中都起着重要的作用。此外, 我们最新公布的和未公布的数据表明，JCV晚期Agno 蛋白质和抗原似乎也在这两种病毒基因中起着调节作用。 与病毒和细胞相互作用的表达和DNA复制 蛋白质，特别是T抗原和YB-1。因此，我们在这里建议调查 官能团调控JCV的分子机制 T抗原、AgNO和YB-1之间的相互作用。通过运用分子生物学， 遗传学和病毒学方法，我们将i)进行彻底的分子 病毒学研究确定AgNO在JCV基因调控中的作用 通过检测其物理和功能来转录和复制 与T抗原和YB-1的相互作用；II)研究功能重要性 AgNO早期异位表达对AgNO病毒裂解周期的影响 感染突变分析和；iii)表征潜在的 Agno蛋白的磷酸化位点及其在JCV寿命中的作用 周而复始。这些综合研究的结果将提供有价值的 JCV基因调控和JCV基因调控的潜在机制 复制；从而促进JCV诱导的中枢神经系统疾病的进展。

DESCRIPTION (provided by applicant): Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) resulting from the lytic infection of oligodendrocytes by the human polyomavirus, JC virus (PML was once considered a rare complication of middle-aged and elderly patients with lymphoprolifera diseases. In recent years, however, increasingly high incidence of PML in AIDS patients than those wit immunosuppressive disorders led us to believe that PML may also be regarded as a AIDS-associated disease. Lytic phase of JCV appears to be highly complex and remains elusive. A growing body of experimental evidence suggests that the regulation of JC viral gene expression and replication is not mediated solely by the presence absence of a particular transcription factor in a given cell. Rather delicate interactions among transcription or interactions between host and viral regulatory proteins appear to be important determining factors in respect. In support of this hypothesis, we have recently presented evidence of specific functional interactions between a cellular factor, YB-1, and JCV T-antigen and showed that both proteins play important roles in J expression. In addition, our most recent published and unpublished data indicate that JCV late Agno protein, antigen, also appears to have regulatory roles in both viral gene expression and DNA replication through interaction with viral and cellular proteins, notably with T-antigen and YB-1. Hence, here we propose investigate the molecular mechanisms involved in regulation of JCV by the functional interplay between T-antigen, Agno and YB-1. By employing molecular biology, genetics and virological approaches, we will i) perform thorough molecular virological studies to determine the role of Agno in regulation of JCV gene transcription and replication by examining its physical and functional interaction with T-antigen and YB- 1; ii) investigate the function importance of Agno viral lytic cycle by means of both ectopic expression of Agno early in infection mutational analysis and; iii) characterize the potential phosphorylation sites of Agno protein and investigate the role in JCV life cycle. The results from such comprehensive studies will provide valuable information underlying mechanisms involved in both JCV gene regulation and replication; and thereby the progression of JCV-induced CNS disease.