Translational induction of the inhibitor of apoptosis protein HIAP2 during endoplasmic reticulum stress attenuates cell death and is mediated via an inducible internal ribosome entry site element.

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.