Translational and post‐translational regulation of XIAP by eIF2α and ATF4 promotes ER stress‐induced cell death during the unfolded protein response (151.5)

Chronic endoplasmic reticulum (ER) stress causes cell death and contributes to disease pathogenesis and progression. ER stress activates intracellular signaling pathways termed the Unfolded Protein Response (UPR). The mechanisms by which chronic ER stress and UPR promote cell death are poorly understood. The PERK arm of the UPR has been implicated in the induction of cell death through its upregulation of proapoptotic CHOP transcription factor. Chop‐/‐ cells are only partially resistant to ER stress‐induced apoptosis, and CHOP overexpression alone does not induce apoptosis. These findings strongly suggest that additional mechanisms are involved in regulating cell death downstream of PERK. Here, we find chronic ER stress dramatically suppresses XIAP protein levels. We find that PERK signaling is responsible for suppressing XIAP by eIF2a‐dependent translational attenuation and ATF4‐mediated proteasomal degradation. PERK’s down‐regulation of XIAP occurs independently of CHOP. Loss of XIAP leads to increased cell death, while XIAP overexpression significantly enhances resistance to ER stress‐induced cell death, even in the absence of CHOP. We propose a “two‐hit” model of ER stress‐induced apoptosis involving concomitant CHOP upregulation and XIAP down‐regulation both regulated by PERK.