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Down-regulation of p53 by double-stranded RNA modulates the antiviral response

Joao T Marques1, Dominique Rebouillat, Chilakamarti V Ramana

  • 1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA.

Journal of Virology
|August 17, 2005
PubMed

Insights

Viral infection down-regulates the tumor suppressor p53, which is crucial for triggering apoptosis and limiting viral replication. This process involves double-stranded RNA and PKR/RNase L pathways.

Area of Science:

  • Virology
  • Molecular Biology
  • Immunology

Background:

  • The tumor suppressor p53's role in antiviral defense is not fully understood.
  • Previous studies suggest p53 activation by interferons and vesicular stomatitis virus (VSV).
  • However, other viruses like encephalomyocarditis virus (EMCV) and human parainfluenza virus type 3 (HPIV3) induce p53 down-regulation.

Purpose of the Study:

  • To investigate the role of p53 in antiviral defense.
  • To elucidate the mechanism by which viral infection affects p53 levels.
  • To determine the impact of p53 down-regulation on viral replication and host cell fate.

Main Methods:

  • Induction of p53 down-regulation using non-oncogenic viruses (EMCV, HPIV3) and double-stranded RNA (dsRNA) mimics.
  • Utilizing a mutant vaccinia virus lacking the E3L protein to study dsRNA's role.
  • Assessing viral replication in wild-type (WT) and p53 knockout (KO) cells.
  • Performing cell cycle analysis and apoptosis assays following dsRNA treatment.

Main Results:

  • Viral infection and dsRNA trigger p53 down-regulation via PKR and RNase L mediated translation inhibition.
  • p53 down-regulation enhances VSV replication but retards EMCV and HPIV3 replication.
  • WT cells exhibit an early-G1 arrest upon dsRNA treatment, while p53 KO cells do not.
  • Apoptosis is initiated in WT cells after p53 down-regulation, whereas p53 KO cells undergo rapid apoptosis.

Conclusions:

  • p53 down-regulation by viral dsRNA is a key mechanism in antiviral response.
  • This down-regulation facilitates apoptosis, which is essential for limiting viral replication.
  • The interplay between p53, apoptosis, and viral replication highlights a novel aspect of tumor suppressor function in immunity.

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