SMAD proteins of oligodendroglial cells regulate transcription of JC virus early and late genes coordinately with the Tat protein of human immunodeficiency virus type 1.
SMAD proteins of oligodendroglial cells regulate transcription of JC virus early and late genes coordinately with the Tat protein of human immunodeficiency virus type 1.
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少突胶质细胞的 SMAD 蛋白与人类免疫缺陷病毒 1 型的 Tat 蛋白协调调节 JC 病毒早期和晚期基因的转录。
DOI：
10.1099/vir.0.011072-0
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Johnson,EdwardM
中科院分区：
文献类型：
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作者：
Stettner,MichelleR;Nance,JonasA;Wright,ClaytonA;Kinoshita,Yayoi;Kim,Woong-Ki;Morgello,Susan;Rappaport,Jay;Khalili,Kamel;Gordon,Jennifer;Johnson,EdwardM
JC病毒（JCV）是进行性多灶性脑白质病（PML）的病原，PML是一种影响艾滋病患者的致命的脑脱髓鞘疾病。虽然免疫抑制参与了JCV对大脑的感染，但人类免疫缺陷病毒1型（HIV-1）的直接影响也已被确立。HIV-1的Tat蛋白参与了HIV-1感染细胞中细胞因子转化生长因子(TGF)-β的激活，以及刺激少突胶质细胞中JCV基因转录和DNA复制，少突胶质细胞是PML中感染JCV的主要中枢神经系统细胞类型。本研究表明Tat可与TGF-β细胞内效应因子SMAD蛋白在JCV DNA控制区（CR）协同刺激JCV基因转录。当通过转染或外源添加表达时，可刺激KG-1少突胶质细胞中的JCV早期基因转录。通过染色质免疫沉淀，我们发现外源Tat增强了SMAD2、-3和-4及其结合伙伴Fast1与活细胞中JCV CR的结合。当SMAD2、-3和-4同时表达时，由质粒pTat表达的Tat同时刺激了早期和晚期基因启动子的转录，其中早期启动子对>的刺激达到100倍。此外，SMAD4和JCV大t抗原均可见于大脑额叶活动性PML病变边缘的少突胶质细胞。这些结果揭示了TGF-β系统的SMAD介质与Tat协同作用刺激JCV基因转录的正强化系统。
JC virus (JCV) is the aetiological agent of progressive multifocal leukoencephalopathy (PML), a fatal, demyelinating disease of the brain affecting people with AIDS. Although immunosuppression is involved in infection of the brain by JCV, a direct influence of human immunodeficiency virus type 1 (HIV-1) has also been established. The Tat protein of HIV-1 has been implicated in activation of the cytokine transforming growth factor (TGF)-βin HIV-1-infected cells and in stimulating JCV gene transcription and DNA replication in oligodendroglia, the primary central nervous system cell type infected by JCV in PML. This study demonstrated that Tat can cooperate with SMAD proteins, the intracellular effectors of TGF-β, at the JCV DNA control region (CR) to stimulate JCV gene transcription. Tat stimulated JCV early gene transcription in KG-1 oligodendroglial cells when expressed via transfection or added exogenously. Using chromatin immunoprecipitation, it was shown that exogenous Tat enhanced binding of SMAD2, -3 and -4 and their binding partner Fast1 to the JCV CR in living cells. When SMAD2, -3 and -4 were expressed together, Tat, expressed from plasmid pTat, stimulated transcription from both early and late gene promoters, with the early promoter exhibiting stimulation of >100-fold. Tat, SMAD4 and JCV large T-antigen were all visualized in oligodendroglial cells at the border of an active PML lesion in the cerebral frontal lobe. These results revealed a positive reinforcement system in which the SMAD mediators of the TGF-βsystem act cooperatively with Tat to stimulate JCV gene transcription.