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

Hassen S Wollebo1, Sonia Melis, Kamel Khalili

  • 1Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA 19140, USA.

Virology
|July 4, 2012
PubMed

Insights

Human polyomavirus JC (JCV) causes progressive multifocal leukoencephalopathy (PML). NFAT4 and NF-κB proteins interact to activate JCV transcription and DNA replication, a process regulated by C/EBPβ.

Area of Science:

  • Neurovirology
  • Molecular Biology
  • Immunology

Background:

  • Human polyomavirus JC (JCV) causes the fatal CNS demyelinating disease progressive multifocal leukoencephalopathy (PML).
  • JCV infection is common, with the virus persisting in a latent state, yet PML is rare, indicating tight viral regulation.
  • Previous work identified NF-κB and C/EBPβ as regulators of JCV promoters, influenced by inflammatory cytokines like TNF-α.

Purpose of the Study:

  • To investigate the role of NFAT4 in JCV gene regulation.
  • To elucidate the interaction between NFAT4, NF-κB, and other regulatory factors at the JCV KB element.
  • To understand the mechanisms controlling JCV latency and reactivation.

Main Methods:

  • Co-immunoprecipitation assays to detect protein-protein interactions.
  • Reporter gene assays to measure transcriptional activity of JCV promoters.
  • Analysis of viral DNA replication in response to regulatory factor manipulation.
  • Inhibition studies using calcineurin/NFAT pathway blockers.

Main Results:

  • NFAT4 and NF-κB were found to interact at the JCV KB element.
  • This interaction leads to co-operative activation of both JCV early and late transcription.
  • NFAT4 and NF-κB also co-operatively enhance JCV viral DNA replication.
  • C/EBPβ and calcineurin/NFAT pathway inhibitors block this NFAT4-NF-κB interplay.

Conclusions:

  • NFAT4 and NF-κB play a critical co-activational role in regulating JCV transcription and replication.
  • C/EBPβ acts as an inhibitor in this regulatory complex.
  • The calcineurin/NFAT pathway is crucial for JCV reactivation.
  • These findings provide insights into the molecular mechanisms governing JCV latency and reactivation.

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