Apoptosis plays a major role in normal organism development, tissue homeostasis, and removal of damaged cells and is caused by the activation of proteolytic enzymes termed caspases. Proteins that comprise the Bcl-2 family appear to control the activation of these enzymes. One such protein BIK was recently identified as an endoplasmic reticulum (ER)-residing pro-apoptotic member of the Bcl-2 homology domain-3 (BH3)-only group of the Bcl-2 family that stimulates mitochondrial release of cytochrome c following p53 induction of apoptosis. A significant fraction of BIK is found as an ER transmembrane protein, with most of the protein facing the cytosol. Restricting BIK to the ER membrane by replacing the transmembrane region with that of the ER-selective membrane anchor of cytochrome b resulted in a decreased cytochrome c release from mitochondria and a corresponding drop in cell death. Recent evidence suggests that BIK cooperates with NOXA, another BH3-only protein, to somehow enhance the activation of Bax to stimulate the rapid release of cytochrome c from mitochondria.
