Fig. 9. Model for protein synthesis regulation (through eIF4G) of somatic and germ cell apoptosis. In human somatic undergoing apoptosis, eIF4Gs (including
p97) are cleaved by caspase-3. The cleavage products support a positive feedback loop that commits the cell to irreversible programmed suicide. This loop is initiated by an insult that disrupts the anti-apoptotic functions of Bcl-2, promoting the formation of apoptosomes from Apaf-1 subunits and sequential activation of a caspase cascade. Caspase-3 causes disruption of the cap-dependent translation initiation complex and further promotes the cap-independent synthesis of Apaf-1 and other apoptotic proteins via internal ribosome entry sites (IRESs) in their mRNAs. In C. elegans germ cells, natural variation or genetic disruption [
p170(RNAi)] of the cellular balance (depicted as the
p170/p130 ratio) between cap-dependent and cap-independent IFG-1 isoforms can initiate apoptosis. Data presented here demonstrate that the caspase cascade is affected upstream (likely at CED-4) by eIF4G cleavage. Additionally, IFG-1
p170 is a direct substrate for CED-3, and processed into a
p130-like fragment. Accumulation of the cap-independent fragment may then mimic the function of native
p130 to secondarily enhance the synthesis of CED-4 protein. Therefore, a similar positive feedback loop may guide the natural selection of oocytes for apoptosis as a function of their translational activity.