The caspase-cleaved DAP5 protein supports internal ribosome entry site-mediated translation of death proteins.
Apoptosis is characterized by a translation switch from cap-dependent to internal ribosome entry site (IRES)-mediated protein translation. During apoptosis, several members of the eukaryotic initiation factor (eIF)4G family are cleaved specifically by caspases. Here we investigated which of the caspase-cleaved eIF4G family members could support cap-independent translation through IRES elements that retain activity in the dying cell. We focused on two major fragments arising from the cleavage of eIF4GI and death-associated protein 5 (DAP5) proteins (eIF4GI M-FAG/p76 and DAP5/p86, respectively), because they are the only potential candidates to preserve the minimal scaffold function needed to mediate translation. Transfection-based experiments in cell cultures indicated that expression of DAP5/p86 in cells stimulated protein translation from the IRESs of c-Myc, Apaf-1, DAP5, and XIAP. In contrast, these IRESs were refractory to the ectopically expressed eIF4GI M-FAG/p76. Furthermore, our study provides in vivo evidence that the caspase-mediated removal of the C-terminal tail of DAP5/p97 relieves an inhibitory effect on the protein's ability to support cap-independent translation through the DAP5 IRES. Altogether, the data suggest that DAP5 is a caspase-activated translation factor that mediates translation through a repertoire of IRES elements, supporting the translation of apoptosis-related proteins.
Henis-Korenblit
Sivan
S
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Shani
Gidi
G
Sines
Tal
T
Marash
Lea
L
Shohat
Galit
G
Kimchi
Adi
A
D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D039603:Eukaryotic Initiation Factor-4G; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D008954:Models, Biological; D010448:Peptide Initiation Factors / Q000378:metabolism / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D014162:Transfection
C491300:EIF4G2 protein, human; D039603:Eukaryotic Initiation Factor-4G; D008164:Luminescent Proteins; D010448:Peptide Initiation Factors; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D020169:Caspases