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E1B and E4 oncoproteins of adenovirus antagonize the effect of apoptosis inducing factor

Roberta L Turner1, John C Wilkinson2, David A Ornelles1

  • 1Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.

Virology
|June 4, 2014
PubMed

Insights

Adenovirus infection triggers DNA damage, leading to nuclear fragmentation via apoptosis-inducing factor (AIF) release. Adenoviral E1B-55K and E4orf3 genes prevent this process by inhibiting poly(ADP-ribose) polymerase-1 (PARP-1) activation.

Area of Science:

  • Virology
  • Cell Biology
  • Molecular Biology

Background:

  • Adenovirus infection introduces viral DNA into host cells, stimulating cellular responses.
  • Adenoviral early genes E1B and E4 typically antagonize these cellular responses.
  • A double-mutant adenovirus lacking E1B-55K and E4orf3 fails to suppress the DNA-damage response.

Purpose of the Study:

  • To investigate the mechanism of nuclear fragmentation in cells infected with a double-mutant adenovirus.
  • To determine the role of apoptosis-inducing factor (AIF) and poly(ADP-ribose) polymerase-1 (PARP-1) in viral DNA-induced nuclear damage.

Main Methods:

  • Infection of cells with wild-type and double-mutant group C adenovirus.
  • Analysis of cellular morphology, nuclear fragmentation, and AIF localization.
  • Assessment of PARP-1 activity and the effect of PARP-1 inhibition.
  • Evaluation of AIF-deficient cells.

Main Results:

  • Cells infected with the double-mutant virus exhibited significant morphological heterogeneity and nuclear fragmentation.
  • Nuclear fragmentation was mediated by the translocation of AIF from mitochondria to the nucleus.
  • AIF release was dependent on activated PARP-1, triggered by viral DNA replication.
  • Adenoviral E1B-55K or E4orf3 proteins independently inhibited nuclear fragmentation after PARP-1 activation.

Conclusions:

  • Adenoviral E1B-55K and E4orf3 proteins are crucial for suppressing the DNA-damage response and preventing nuclear fragmentation.
  • The viral DNA-induced nuclear fragmentation pathway involves AIF release dependent on PARP-1 activation.
  • Adenoviral proteins may modulate the distribution of PAR-modified proteins to counteract this process.
Keywords:
AdenovirusApoptosis inducing factorE1B-55KE4orf3Nuclear morphologyPoly (ADP-ribose) polymerase-1

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