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The vaccinia virus B1R kinase induces p53 downregulation by an Mdm2-dependent mechanism

Cláudio R Santos1, Francisco M Vega, Sandra Blanco

  • 1Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, E-37007 Salamanca, Spain.

Virology
|October 7, 2004
PubMed

Insights

The vaccinia virus B1R kinase targets and hyperphosphorylates the host protein p53, leading to its degradation and reduced transcriptional activity. This interaction is crucial for viral pathogenesis and impacts host cell functions.

Area of Science:

  • Virology
  • Molecular Biology
  • Cellular Biology

Background:

  • Poxvirus infections significantly alter host cellular functions.
  • Understanding viral protein interactions with host proteins is key to viral pathogenesis.
  • The vaccinia virus B1R kinase is essential for viral DNA synthesis and replication, but its cellular targets remain unknown.

Purpose of the Study:

  • To identify the cellular substrate of the vaccinia virus B1R kinase.
  • To elucidate the mechanism by which B1R affects host protein function.
  • To understand the role of B1R in vaccinia virus pathogenesis.

Main Methods:

  • In vitro kinase assays to assess B1R activity on p53.
  • Site-directed mutagenesis to investigate the role of specific p53 residues (Ser15, Thr18).
  • Western blotting and immunoprecipitation to analyze p53 ubiquitination, acetylation, and degradation.
  • Quantitative PCR to measure the transcriptional activity of p53 target genes.

Main Results:

  • B1R kinase hyperphosphorylates p53 at N-terminal residues Ser15 and Thr18.
  • B1R promotes p53 ubiquitination and reduces p53 acetylation by p300.
  • Overexpressed B1R induces p53 degradation in a concentration-dependent manner, requiring Mdm2.
  • B1R-mediated hyperphosphorylation of p53 reduces its transcriptional activity, particularly affecting the BAX gene promoter.

Conclusions:

  • The vaccinia virus B1R kinase targets and modifies host protein p53.
  • B1R-induced p53 downregulation is a mechanism by which vaccinia virus manipulates host cell functions.
  • This interaction highlights a novel aspect of viral pathogenesis and host-pathogen interactions.

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