Abstract
Apoptosis is a natural process during animal development for the programmed removal of superfluous cells. During apoptosis general protein synthesis is reduced, but the synthesis of cell death proteins is enhanced. Selective translation has been attributed to modification of the protein synthesis machinery to disrupt cap-dependent mRNA translation and induce a cap-independent mechanism. We have previously shown that disruption of the balance between cap-dependent and cap-independent C. elegans eIF4G isoforms (IFG-1 p170 and p130) by RNA interference promotes apoptosis in developing oocytes. Germ cell apoptosis was accompanied by the appearance of the Apaf-1 homolog, CED-4. Here we show that IFG-1 p170 is a native substrate of the worm executioner caspase, CED-3, just as mammalian eIF4GI is cleaved by caspase-3. Loss of Bcl-2 function (ced-9ts) in worms induced p170 cleavage in vivo, coincident with extensive germ cell apoptosis. Truncation of IFG-1 occurred at a single site that separates the cap-binding and ribosome-associated domains. Site-directed mutagenesis indicated that CED-3 processes IFG-1 at a non-canonical motif, TTTD456. Coincidentally, the recognition site was located 65 amino acids downstream of the newly mapped IFG-1 p130 start site suggesting that both forms support cap-independent initiation. Genetic evidence confirmed that apoptosis induced by loss of ifg-1 p170 mRNA was caspase (ced-3) and apoptosome (ced-4/Apaf-1) dependent. These findings support a new paradigm in which modal changes in protein synthesis act as a physiological signal to initiate cell death, rather than occur merely as downstream consequences of the apoptotic event.
Highlights
During programmed cell death, cells commit to the systematic disassembly of their metabolic framework
We propose that protein synthesis mechanism and eIF4G isoforms play an active role in the decision-making process between growth and apoptosis in germ cells
The initial phases of apoptosis induced by somatic cell damage are marked by a substantial quantitative decrease in protein synthesis activity [37,38,39]
Summary
During programmed cell death (apoptosis), cells commit to the systematic disassembly of their metabolic framework. The eukaryotic translation initiation factor 4 (eIF4) complex catalyzes the joining of mRNA to ribosomes. The basic complex (eIF4F) is comprised of eIF4E, which binds the 7methylguanosine cap, eIF4A, an mRNA helicase, and eIF4G, a scaffold protein that coordinates these factors and bridges the interaction between the mRNA and the 40S ribosomal subunit [2,3]. During apoptosis proteolytic enzymes called caspases induce a signaling cascade that results in cleavage of several translation initiation proteins including eIF2 alpha and eIF4G [4,5]. The cap- and poly(A)-associating N-terminal domain is removed from the RNA/ribosome-binding central domain. The latter complex still catalyzes initiation by a cap-independent mechanism. Translation of mRNAs required for rapid responses to stress depends on the translational competence of eIF4F factors like eIF4G
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