REGULATION OF ENDOPLASMIC RETICULUM STRESS-INDUCED CELL DEATH BY PRO-APOPTIC BOK

MARCOS A. CARPIO; JESSICA SU; MICHAEL MICHAUD; BARBARA EHRLICH; SAMUEL G. KATZ

Cold Spring Harbor, New York

Congreso; CELL DEATH, UNLOCKING DEATH?S MYSTERIES; 2015

Cold Spring Harbor Laboratory

BCL-2 family members regulate apoptosis in response to a diverse array ofsignals. While many family members regulate mitochondrial outermembrane permeabilization (MOMP) by BAX and BAK, some contributeto cell death decisions at other cellular locations. For example, in additionto the MOM, BAX and BAK localize to the Endoplasmic Reticulum (ER),where they control apoptosis through various mechanisms, such asregulation of the unfolded protein response. Primarily found in the ER,BOK is a multidomain, proapoptotic BAX/BAK homologue. In order tobetter understand BOK?s function, we have disrupted the Bok locus. Thecells derived from these mice, as well as the mice themselves, displayselective and quantitative defects in their apoptotic response to several ERstress-inducing stimuli both in vitro and in vivo. Although ER stressappropriately activates the unfolded protein response (UPR) in BOKdisruptedcells as measured by levels of PERK and eIF2-alphaphosphorylation, downstream effector signaling, including activation ofATF4 and CHOP, was defective. A second manner in which BAX andBAK regulate apoptosis from the ER is through regulation of the type 1inositol triphosphate receptor (IP3R) and calcium. Whereas BAX and BAKdo not bind to the IP3R, a recent report has identified BOK as an IP3Rinteraction partner. Here, we have confirmed that BOK binds to the IP3R1and explored the functional consequences of BOK disruption on cellularcalcium homeostasis. These findings suggest multiple roles for BOK inregulating the apoptotic response to ER stress.