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The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus

J E Strong1, M C Coffey, D Tang

  • 1Department of Microbiology and Infectious Diseases, University of Calgary Health Sciences Centre, Calgary, Alberta, Canada T2N 4N1.

The EMBO Journal
|June 17, 1998
PubMed

Insights

NIH-3T3 cells resist reovirus infection until Ras transformation. This transformation blocks viral protein synthesis inhibition by double-stranded RNA-activated protein kinase (PKR), enabling viral replication and oncolysis.

Area of Science:

  • Virology
  • Cell Biology
  • Molecular Biology

Background:

  • NIH-3T3 cells exhibit resistance to reovirus infection.
  • Viral proliferation is restricted at the protein synthesis level, not transcription.
  • Transformation with Ras or Sos confers susceptibility to reovirus.

Purpose of the Study:

  • To investigate the mechanism of reovirus resistance in NIH-3T3 cells.
  • To identify the cellular factors involved in reovirus replication control.
  • To elucidate the role of the Ras signaling pathway in reovirus oncolysis.

Main Methods:

  • Cell transformation using activated Sos or Ras.
  • Analysis of viral gene transcription and protein synthesis.
  • Identification and characterization of a 65 kDa phosphorylated protein in cell lysates.
  • Inhibition of protein kinase R (PKR) phosphorylation using 2-aminopurine or gene deletion.

Main Results:

  • Transformed NIH-3T3 cells (Sos or Ras) became susceptible to reovirus.
  • Reovirus proliferation was inhibited at the protein synthesis stage in untransformed cells.
  • A 65 kDa protein, identified as double-stranded RNA-activated protein kinase (PKR), was phosphorylated in infected untransformed cells, inhibiting translation.
  • PKR phosphorylation was blocked in transformed cells, allowing viral protein synthesis.
  • Inhibition of PKR phosphorylation enhanced reovirus protein synthesis in untransformed cells.

Conclusions:

  • Reovirus infection triggers PKR phosphorylation in untransformed cells, inhibiting viral translation.
  • The Ras signaling pathway in transformed cells blocks PKR phosphorylation, facilitating viral protein synthesis.
  • Ras pathway usurpation is the basis for reovirus oncolysis.

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