The p35 Family of Apoptosis Inhibitors

Cells often respond to viral infection by activating a cellular suicide process, limiting viral replicative potential and hence minimising the spread of the infection. This cellular self-destruction, termed apoptosis, occurs in a tightly regulated, morphologically and biochemically defined manner. To counter this host response to infection, some viruses have evolved molecular strategies to evade apoptosis by encoding proteins that inhibit components of the host's apoptotic machinery. The first identified member of the p35 family, encoded by an insect virus genome, was cloned by virtue of its ability to inhibit insect cell death induced by viral infection. Many insect viruses carry p35 genes and numerous studies have indicated that p35 proteins can suppress a wide variety of cell death stimuli in cells of evolutionarily divergent organisms. A second member of the p35 family, p49, has also recently been cloned and characterised. Like p35, p49 was originally isolated as an inhibitor of infection mediated insect cell death but can also suppress other apoptotic stimuli. Members of the p35 family suppress apoptosis by inhibiting caspases, a family of cysteine proteases that constitute the effector arm of cell death pathways, through a substrate-inhibitor mechanism. This article reviews the anti-apoptotic capacities of members of the p35 family and the mechanism of action underlying their pro-survival activity. Insights into the molecular regulation of apoptosis gained through experimental approaches exploiting p35 family members are also discussed.