Bcl-2 family proteins are recognized as major regulators of the mitochondrial pathway of apoptosis. They control the mitochondrial outer membrane permeabilization (MOMP) by directly localizing to this organelle. Further investigations demonstrated that Bcl-2 related proteins are also found in other intracellular compartments such as the endoplasmic reticulum, the Golgi apparatus, the nucleus and the peroxisomes. At the level of these organelles, Bcl-2 family proteins not only regulate MOMP in a remote fashion but also participate in major cellular processes including calcium homeostasis, cell cycle control and cell migration. With the advances of live cell imaging techniques and the generation of fluorescent recombinant proteins, it became clear that the distribution of Bcl-2 proteins inside the cell is a dynamic process which is profoundly affected by changes in the cellular microenvironment. Here, we describe the current knowledge related to the subcellular distribution of the Bcl-2 family of proteins and further emphasize on the emerging concept that this highly dynamic process is critical for cell fate determination.

In metazoans, Bcl-2 family proteins are major regulators of mitochondrially mediated apoptosis; however, their evolution remains poorly understood. Here, we describe the molecular characterization of the four members of the Bcl-2 family in the most primitive metazoan, Trichoplax adhaerens. All four trBcl-2 homologs are multimotif Bcl-2 group, with trBcl-2L1 and trBcl-2L2 being highly divergent antiapoptotic Bcl-2 members, whereas trBcl-2L3 and trBcl-2L4 are homologs of proapoptotic Bax and Bak, respectively. trBax expression permeabilizes the mitochondrial outer membrane, while trBak operates as a BH3-only sensitizer repressing antiapoptotic activities of trBcl-2L1 and trBcl-2L2. The crystal structure of a trBcl-2L2:trBak BH3 complex reveals that trBcl-2L2 uses the canonical Bcl-2 ligand binding groove to sequester trBak BH3, indicating that the structural basis for apoptosis control is conserved from T. adhaerens to mammals. Finally, we demonstrate that both trBax and trBak BH3 peptides bind selectively to human Bcl-2 homologs to sensitize cancer cells to chemotherapy treatment.