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Identifying Dysregulated Genes Induced by Kaposi's Sarcoma-associated Herpesvirus (KSHV)
07:02

Identifying Dysregulated Genes Induced by Kaposi's Sarcoma-associated Herpesvirus (KSHV)

Published on: September 14, 2010

Kaposi's sarcoma-associated herpesvirus LANA protein downregulates nuclear glycogen synthase kinase 3 activity and

Jianyong Liu1, Heather Martin, Meir Shamay

  • 1Johns Hopkins University School of Medicine, Bunting-Blaustein Building CRB308, 1650 Orleans Street, Baltimore, MD 21231, USA.

Journal of Virology
|February 23, 2007
PubMed

Insights

Kaposi's sarcoma-associated herpesvirus LANA protein inactivates nuclear GSK-3 by recruiting ERK1/2 and RSK1. This LANA-mediated GSK-3 inactivation inhibits C/EBP phosphorylation, impairing cell differentiation.

Area of Science:

  • Virology
  • Cell Biology
  • Molecular Biology

Background:

  • Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) interacts with glycogen synthase kinase 3 (GSK-3).
  • This interaction leads to beta-catenin stabilization and upregulation of beta-catenin-responsive genes.

Purpose of the Study:

  • To investigate the downstream consequences of the LANA-GSK-3 interaction.
  • To elucidate the mechanism by which LANA affects nuclear GSK-3 activity and its substrates.

Main Methods:

  • Co-immunoprecipitation assays to detect protein interactions.
  • In vitro kinase assays to assess LANA as a substrate.
  • Analysis of GSK-3 substrate phosphorylation in LANA-expressing cells.
  • Modeling differentiation in 3T3L1 adipogenesis system.

Main Results:

  • Nuclear GSK-3 bound to LANA is enriched in its inactive, serine 9-phosphorylated form.
  • LANA recruits extracellular signal-regulated kinases 1 and 2 (ERK1/2) and ribosomal S6 kinase 1 (RSK1) for GSK-3 inactivation.
  • LANA expression impairs the phosphorylation of GSK-3 substrates C/EBPbeta and C/EBPalpha.
  • LANA-expressing 3T3L1 cells show impaired adipogenesis and delayed/reduced induction of C/EBPbeta targets.

Conclusions:

  • LANA inactivates nuclear GSK-3 through recruitment of ERK1/2 and RSK1.
  • This inactivation modifies the function of GSK-3 substrates, including C/EBPs.
  • LANA-mediated inhibition of C/EBP phosphorylation results in impaired cell differentiation.

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