Vaccinia-induced epidermal growth factor receptor-MEK signalling and the anti-apoptotic protein F1L synergize to suppress cell death during infection.
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.
Postigo
Antonio
A
Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Martin
Morag C
MC
Dodding
Mark P
MP
Way
Michael
M
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D003561:Cytarabine / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D010455:Peptides / Q000378:metabolism; D014615:Vaccinia / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D014616:Vaccinia virus / Q000187:drug effects / Q000472:pathogenicity* / Q000502:physiology; D014764:Viral Proteins / Q000378:metabolism*; D014774:Virulence; D014779:Virus Replication; D051025:bcl-Associated Death Protein / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; C494819:BAD protein, human; C507356:F1L protein, vaccinia virus; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D014764:Viral Proteins; D051025:bcl-Associated Death Protein; C051087:vaccinia growth factor; D003561:Cytarabine; D004815:Epidermal Growth Factor