JCPyV T-Antigen Activation of the Anti-Apoptotic Survivin Promoter-Its Role in the Development of Progressive Multifocal Leukoencephalopathy.
JCPyV T-Antigen Activation of the Anti-Apoptotic Survivin Promoter-Its Role in the Development of Progressive Multifocal Leukoencephalopathy.
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DOI：
10.3390/v12111253
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发表时间：
2020-11-03
期刊：
影响因子：
--
通讯作者：
Piña-Oviedo S
中科院分区：
文献类型：
--
作者：
Del Valle L;Sweet T;Parker-Struckhoff A;Perez-Liz G;Piña-Oviedo S
进行性多灶性白质脑病（PML）是一种致命的CNS脱髓鞘疾病，由人嗜神经性多瘤病毒JC（JCPyV）溶解性感染少突胶质细胞引起，通常与严重的免疫功能低下状态相关，近年来与免疫治疗的使用相关。细胞凋亡是一种稳态机制，用于处理衰老或受损的细胞，包括病毒感染的细胞，在绝大多数脑病毒感染中触发。以前，我们在PML病例中发现了正常休眠的抗凋亡蛋白Survivin的上调，这在体外导致了JCPyV感染的星形胶质细胞和少突胶质细胞的原代培养物免于凋亡。在本研究中，我们首先证明了在16例PML中没有凋亡DNA片段和缺乏caspase活性。我们还鉴定了病毒蛋白大T抗原作为负责激活Survivin启动子的蛋白。染色质免疫沉淀分析显示T抗原与Survivin启动子DNA之间的直接结合。最后，我们已经确定了T抗原的特定区域，跨越氨基酸266和688，其结合Survivin并将其易位到细胞核，提供了导致JCPyV有效复制的机制的证据和新疗法的潜在靶点。
Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the CNS, resulting from the lytic infection of oligodendrocytes by the human neurotropic polyomavirus JC (JCPyV), typically associated with severe immunocompromised states and, in recent years, with the use of immunotherapies. Apoptosis is a homeostatic mechanism to dispose of senescent or damaged cells, including virally infected cells, triggered in the vast majority of viral infections of the brain. Previously, we showed upregulation of the normally dormant anti-apoptotic protein Survivin in cases of PML, which—in vitro—resulted in protection from apoptosis in JCPyV-infected primary cultures of astrocytes and oligodendrocytes. In the present study, we first demonstrate the absence of apoptotic DNA fragmentation and the lack of caspase activity in 16 cases of PML. We also identified the viral protein large T-Antigen as being responsible for the activation of the Survivin promoter. Chromatin Immunoprecipitation assay shows a direct binding between T-Antigen and the Survivin promoter DNA. Finally, we have identified the specific region of T-Antigen, spanning from amino acids 266 and 688, which binds to Survivin and translocates it to the nucleus, providing evidence of a mechanism that results in the efficient replication of JCPyV and a potential target for novel therapies.
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