Regulation of apoptosis by the BAP31 complex at the endoplasmic reticulum

Apoptosis is a genetically programmed, biochemically executed form of cell suicide essential for development and homeostasis in all multicellular organisma. The caspase family of cysteine proteases orchestrate the apoptosis program and are regulated by memebers of the Bcl-2 family. Extensive studies in mammals have revealed that Bcl-2 proteins control caspase activiation by governing a key mitochondrial checkpoint, invovling the permeabilization of the outer mitochondrial membrane and the release of proapoptotic factors from the intermembrane spce. Bcl-2 proteins are located at other intracellular membranes, including the endoplasmic reticulum, and emerging evidence suggests that this organelle also plays a key role in the initiation of poptosis. Here, I identify BAP31, a Bcl-2 associated protein of the ER membrane, as a central regulator of diverse poptosis pathways. In response to signaling by the model oncogene, E1A, BAP31 and its cellular homolog and heterodimerizing partner, BAP29, were found to recruit and activate a novel procaspase-8L isoform at the surface of the ER by a BCL-2-inhibitable mechansim. Cells deficient in Bap31 and Bap29 resisted E1A-induced procaspase-8L activiation, downstream effector caspase activiation, and apoptosis, suggesting that the BAP/procaspase-8L complex plays a critical role in activating the apoptosis program following oncogenic stress. In addition to being a regulator of procaspase-8L, BAP31 was also found to be an important caspase-8 substrate. Caspase-8-induced mitochondrial dysfunction and apoptosis and were strongly inhibited by the expression of a caspase-resistant BAP31 mutant that remained structurally intact during apoptosis. MOreover, the p20 caspase cleavage fragment of BAP31 was found to induce Ca^2+ transmission between the ER and mitochondria, which stimulated the onset of mitchondrial fission and ultimately sensitized this organelle to caspase-8-driven cytochrome c release. Thus, BAP31 appears to be a cell death integrator that couples oncogenic signals to procaspase-8L activiation, and triggers Ca^2+-dependent proapoptotic cross-talk bewteen the ER and mitochondria