Vaccinia-induced epidermal growth factor receptor-MEK signalling and the anti-apoptotic protein F1L synergize to suppress cell death during infection

Cell Microbiol. 2009 Aug;11(8):1208-18. doi: 10.1111/j.1462-5822.2009.01327.x. Epub 2009 Apr 22.


F1L is a functional Bcl-2 homologue that inhibits apoptosis at the mitochondria during vaccinia infection. However, the extent and timing of cell death during DeltaF1L virus infection suggest that additional viral effectors cooperate with F1L to limit apoptosis. Here we report that vaccinia growth factor (VGF), a secreted virulence factor, promotes cell survival independently of its role in virus multiplication. Analysis of single and double knockout viruses reveals that VGF acts synergistically with F1L to protect against cell death during infection. Cell survival in the absence of F1L is dependent on VGF activation of the epidermal growth factor receptor. Furthermore, signalling through MEK kinases is necessary and sufficient for VGF-dependent survival. We conclude that VGF stimulates an epidermal growth factor receptor-MEK-dependent pro-survival pathway that synergizes with F1L to counteract an infection-induced apoptotic pathway that predominantly involves the BH3-only protein Bad.

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology
  • Apoptosis*
  • Cytarabine / pharmacology
  • Epidermal Growth Factor / metabolism*
  • Gene Expression Regulation, Viral / drug effects
  • HeLa Cells
  • Host-Pathogen Interactions
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • MAP Kinase Signaling System*
  • Peptides / metabolism
  • Vaccinia / metabolism
  • Vaccinia / pathology
  • Vaccinia / virology*
  • Vaccinia virus / drug effects
  • Vaccinia virus / pathogenicity*
  • Vaccinia virus / physiology
  • Viral Proteins / metabolism*
  • Virulence
  • Virus Replication
  • bcl-Associated Death Protein / metabolism


  • Antimetabolites, Antineoplastic
  • BAD protein, human
  • F1L protein, vaccinia virus
  • Intercellular Signaling Peptides and Proteins
  • Peptides
  • Viral Proteins
  • bcl-Associated Death Protein
  • vaccinia growth factor
  • Cytarabine
  • Epidermal Growth Factor