PRO-APOPTOTIC BOK REGULATES ENDOPLASMIC RETICULUM CALCIUM LEVELS

MARCOS A. CARPIO; IVANA Y KUO; JESSICA SU; MICHAEL MICHAUD; RUNNING MIAO; BARBARA EHRLICH; SAMUEL G. KATZ

Cork

Congreso; INTERNATIONAL CELL DEATH SOCIETY; 2016

INTERNATIONAL CELL DEATH SOCIETY

The mitochondrial pathway of apoptosis is regulated by BCL-2 family members at multiple points of control. For example, the BCL-2 family effectors BAX and BAK mediate mitochondrial outer membrane permeabilization (MOMP), but are also necessary for maintaining the ER calcium stores necessary for calcium-dependent cell death. BCL-2 Ovarian Killer (BOK) is a member of the BCL-2 protein family that most closely resembles BAX and BAK. Previously, we have shown that BOK promotes cell death in response to ER stress stimuli, such as the proteasome inhibitor bortezomib. This is in agreement with recent observations that proteasome inhibition stabilizes BOK to induce apoptosis. However, the mechanisms by which BOK regulates apoptosis are still incompletely understood. Like BAX and BAK, BOK localizes to the ER in addition to the mitochondria. Moreover, BOK binds strongly and constitutively to inositol 1,4,5-trisphosphate receptors (IP3Rs), which govern the release of ER calcium stores. Here, we have performed live cell calcium imaging in BOK-disrupted cells and have found several defects in cellular calcium homeostasis and stimulus induced regulation. These findings suggest that BOK plays a critical role with IP3Rs in regulating cellular calcium levels, which may impact the cell?s response to ER stress-induced apoptosis.