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PNAS 99 (8): 5400-5405

Copyright © 2002 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

The caspase-cleaved DAP5 protein supports internal ribosome entry site-mediated translation of death proteins

Sivan Henis-Korenblit, Gidi Shani, Tal Sines, Lea Marash, Galit Shohat, and Adi Kimchi*

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel

Accepted for publication February 21, 2002.

Received for publication October 22, 2001.

Abstract: Apoptosis is characterized by a translation switch from capdependent 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.

* To whom reprint requests should be addressed. E-mail: Adi.Kimchi{at}weizmann.ac.il.

Communicated by Leo Sachs, Weizmann Institute of Science, Rehovot, Israel

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