A Novel Form of DAP5 Protein Accumulates in Apoptotic Cells as a Result of Caspase Cleavage and Internal Ribosome Entry Site-Mediated Translation

doi:10.1128/MCB.20.2.496-506.2000

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Molecular and Cellular Biology, January 2000, p. 496-506, Vol. 20, No. 2
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

A Novel Form of DAP5 Protein Accumulates in Apoptotic Cells as a Result of Caspase Cleavage and Internal Ribosome Entry Site-Mediated Translation

Sivan Henis-Korenblit, Naomi Levy Strumpf, Dan Goldstaub, and Adi Kimchi^*

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

Received 1 June 1999/Returned for modification 27 July 1999/Accepted 19 October 1999

Death-associated protein 5 (DAP5) (also named p97 and NAT1) is a member of the translation initiation factor 4G (eIF4G) familythat lacks the eIF4E binding site. It was previously implicatedin apoptosis, based on the finding that a dominant negative fragmentof the protein protected against cell death. Here we address itsfunction and two distinct levels of regulation during apoptosisthat affect the protein both at translational and posttranslationallevels. DAP5 protein was found to be cleaved at a single caspasecleavage site at position 790, in response to activated Fas orp53, yielding a C-terminal truncated protein of 86 kDa that iscapable of generating complexes with eIF4A and eIF3. Interestingly,while the overall translation rate in apoptotic cells was reducedby 60 to 70%, in accordance with the simultaneous degradationof the two major mediators of cap-dependent translation, eIF4GIand eIF4GII, the translation rate of DAP5 protein was selectivelymaintained. An internal ribosome entry site (IRES) element capableof directing the translation of a reporter gene when subclonedinto a bicistronic vector was identified in the 5' untranslatedregion of DAP5 mRNA. While cap-dependent translation from thistransfected vector was reduced during Fas-induced apoptosis, thetranslation via the DAP5 IRES was selectively maintained. Additionof recombinant DAP5/p97 or DAP5/p86 to cell-free systems enhancedpreferentially the translation through the DAP5 IRES, whereasneutralization of the endogenous DAP5 in reticulocyte lysatesby adding a dominant negative DAP5 fragment interfered with thistranslation. The DAP5/p86 apoptotic form was more potent thanDAP5/p97 in these functional assays. Altogether, the data suggestthat DAP5 is a caspase-activated translation factor which mediatescap-independent translation at least from its own IRES, thus generatinga positive feedback loop responsible for the continuous translationof DAP5 duringapoptosis.

^* Corresponding author. Mailing address: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.Phone: 972-8-9342428. Fax: 972-8-9344108. E-mail: lvkimchi{at}weizmann.weizmann.ac.il.

Molecular and Cellular Biology, January 2000, p. 496-506, Vol. 20, No. 2
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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