Prolonged endoplasmic reticulum (ER) stress leads to activation of caspases and cell death. The inhibitor of apoptosis (IAP) proteins are intrinsic inhibitors of apoptosis by virtue of inhibiting distinct caspases and are, therefore, critical regulators of cell death. Here we demonstrate that the expression of one member of the IAP family, HIAP2, is induced in response to ER stress and attenuates ER stress-induced cell death. The induction of HIAP2 is executed at the level of protein synthesis and is mediated by an inducible internal ribosome entry site (IRES) element. The triggering of ER stress results in caspase-mediated proteolytic processing of eukaryotic initiation factor p97/DAP5/NAT1, producing a fragment that specifically activates HIAP2 IRES. These data suggest an existence of a novel mechanism that regulates apoptotic response in ER stress.

DAP5/p97 is a member of the eIF4G family of translation initiation factors that has been suggested to play an important role in the translation of select messenger RNA molecules. We have shown previously that the caspase-cleaved form of DAP5/p97, termed p86, is required for the induction of the endoplasmic reticulum (ER)-stress-responsive internal ribosome entry site (IRES) of the caspase inhibitor HIAP2. We show here that expression of DAP5/p97 is enhanced during ER stress by selective recruitment of DAP5/p97 mRNA into polysomes via the DAP5/p97 IRES. Importantly, enhanced translation mediated by the DAP5/p97 IRES is dependent on DAP5/p97 itself, thus providing a positive feedback loop. In addition, we show that activation of DAP5/p97 and HIAP2 IRES during ER stress requires DAP5/p97. Significantly, the induction of DAP5/p97 during ER stress is caspase-independent, whereas the induction of HIAP2 requires proteolytic processing of DAP5/p97. Thus, DAP5/p97 is a translational activator that selectively modulates translation of specific mRNAs during conditions of cellular stress in both a caspase-dependent and caspase-independent manner.