Cooperative roles of NF-κB and NFAT4 in polyomavirus JC regulation at the KB control element

• Published in: Virology (New York, N.Y.) Vol. 432; no. 1; pp. 146 - 154
• Main Authors: Wollebo, Hassen S, Melis, Sonia, Khalili, Kamel, Safak, Mahmut, White, Martyn K
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.10.2012
• Subjects: CCAAT-Enhancer-Binding Protein-beta - metabolism; Cell Line, Tumor; Gene Expression Regulation, Viral; Host-Pathogen Interactions; Humans; Infectious Disease; JC Virus - genetics; JC Virus - physiology; NF-kappa B - metabolism; NF-kappaB signaling; NFAT signaling; NFATC Transcription Factors - metabolism; Polyomavirus JC; Progressive multifocal leukoencephalopathy; Transcription, Genetic; Transcriptional Activation; Virus Activation; Virus Replication; NFAT signaling; NF-kappaB signaling; Polyomavirus JC; Progressive multifocal leukoencephalopathy
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2012.06.010

Abstract The human polyomavirus JC (JCV) is the causative agent of the CNS demyelinating disease progressive multifocal leukoencephalopathy (PML). Infection by JCV is extremely common and after primary infection, JCV persists in a latent state. However, PML is a very rare disease suggesting that the virus is tightly regulated. Previously, we showed that NF-κB and C/EBPβ regulate the JCV early and late promoters via a DNA control element, KB, which also mediates the stimulatory effects of proinflammatory cytokines such as TNF-α on JCV gene expression. Other studies have implicated NFAT4 in JCV regulation. We now report that NFAT4 and NF-κB interact at the KB element to co-operatively activate both JCV early and late transcription and viral DNA replication. This interplay is inhibited by C/EBPβ and by agents that block the calcineurin/NFAT signaling pathway. The importance of these events in the regulation of JCV latency and reactivation is discussed.