The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus manipulates the activity of glycogen synthase kinase-3β

Masahiro Fujimuro, S. Diane Hayward

Research output: Contribution to journalArticlepeer-review

Abstract

The latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) is expressed in all KSHV-associated malignancies. LANA is essential for replication and maintenance of the viral episomes during latent infection. However, LANA also has a transcriptional regulatory role and can affect gene expression both positively and negatively. A previously performed yeast two-hybrid screen identified glycogen synthase kinase 3 (GSK-3) as a LANA-interacting protein. Interaction with both GSK-3α and GSK-3β was confirmed in transfected cells with coprecipitation assays. GSK-3β also interacted with the herpesvirus saimiri homolog ORF73. GSK-3β is an intermediate in the Wnt signaling pathway and a negative regulator of β-catenin. In transfected cells, LANA was shown to overcome GSK-3β-mediated degradation of β-catenin. Examination of primary effusion lymphoma (PEL) cells found increased levels of β-catenin relative to KSHV-negative B cells, and this translated into increased activity of a β-catenin-responsive reporter containing Tcf/Lef binding sites. In tetradecanoyl phorbol acetate-treated PEL cells, loss of LANA expression correlated temporally with loss of detectable β-catenin. LANA was found to alter the intracellular distribution of GSK-3β so that nuclear GSK-3β was more readily detectable in the presence of LANA. Mapping experiments with coimmunoprecipitation assays revealed that both N-terminal and C-terminal LANA sequences were required for efficient GSK-3β interaction. LANA mutants that were defective for GSK-3β interaction were unable to mediate GSK-3β relocalization or activate a β-catenin-responsive Tcf-luciferase reporter. This study identified manipulation of GSK-3β activity as a mechanism by which LANA may modify transcriptional activity and contribute to the phenotype of primary effusion lymphoma.

Original languageEnglish (US)
Pages (from-to)8019-8030
Number of pages12
JournalJournal of virology
Volume77
Issue number14
DOIs
StatePublished - Jul 2003

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Fingerprint Dive into the research topics of 'The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus manipulates the activity of glycogen synthase kinase-3β'. Together they form a unique fingerprint.

Cite this