Department of Neuroscience, Center for Neurovirology-Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.
Mayo Clinic Hospital and Health Care, 200 First St. S.W., Rochester, MN 55905, USA.
Viruses. 2021 Sep 26;13(10):1937. doi: 10.3390/v13101937.
Polyomavirus JC (JCPyV) causes the demyelinating disease progressive multifocal leukoencephalopathy (PML). JCPyV infection is very common in childhood and, under conditions of severe immunosuppression, JCPyV may reactivate to cause PML. JC viral proteins expression is regulated by the JCPyV non-coding control region (NCCR), which contains binding sites for cellular transcriptional factors which regulate JCPyV transcription. Our earlier studies suggest that JCPyV reactivation occurs within glial cells due to cytokines such as TNF-α which stimulate viral gene expression. In this study, we examined interferon-α (IFNα) or β (IFNβ) which have a negative effect on JCPyV transcriptional regulation. We also showed that these interferons induce the endogenous liver inhibitory protein (LIP), an isoform of CAAT/enhancer binding protein beta (C/EBPβ). Treatment of glial cell line with interferons increases the endogenous level of C/EBPβ-LIP. Furthermore, we showed that the negative regulatory role of the interferons in JCPyV early and late transcription and viral replication is more pronounced in the presence of C/EBPβ-LIP. Knockdown of C/EBPβ-LIP by shRNA reverse the inhibitory effect on JCPyV viral replication. Therefore, IFNα and IFNβ negatively regulate JCPyV through induction of C/EBPβ-LIP, which together with other cellular transcriptional factors may control the balance between JCPyV latency and activation.
多瘤病毒 JC（JCPyV）会引起脱髓鞘疾病进行性多灶性白质脑病（PML）。JCPyV 在儿童中非常常见，在严重免疫抑制的情况下，JCPyV 可能会重新激活导致 PML。JCPyV 蛋白的表达受 JCPyV 非编码调控区（NCCR）调控，该区域包含细胞转录因子的结合位点，这些转录因子调节 JCPyV 的转录。我们之前的研究表明，JCPyV 的重新激活发生在神经胶质细胞中，这是由于细胞因子如 TNF-α刺激病毒基因表达所致。在这项研究中，我们研究了干扰素-α（IFNα）或-β（IFNβ）对 JCPyV 转录调控的负作用。我们还表明，这些干扰素诱导内源性肝抑制蛋白（LIP），即 CAAT/增强子结合蛋白β（C/EBPβ）的同工型。用干扰素处理神经胶质细胞系会增加内源性 C/EBPβ-LIP 水平。此外，我们还表明，在存在 C/EBPβ-LIP 的情况下，干扰素对 JCPyV 早期和晚期转录以及病毒复制的负调控作用更为明显。通过 shRNA 敲低 C/EBPβ-LIP 可逆转对 JCPyV 病毒复制的抑制作用。因此，IFNα 和 IFNβ 通过诱导 C/EBPβ-LIP 负调控 JCPyV，C/EBPβ-LIP 与其他细胞转录因子一起可能控制 JCPyV 潜伏和激活之间的平衡。
