Subcellular Localization and Dynamics of the Bcl-2 Family of Proteins

Abstract

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.

Keywords: Bcl-2 family; endoplasmic reticulum; mitochondria; nucleus; subcellular localization.

Figure 1

Classification of Bcl-2 family of proteins in respect to their subcellular localizations. Bcl-2 family members were classified based on their implication in the MOMP. The presence of conserved Bcl-2 homology (BH) and transmembrane (TM) domains were indicated with color dots. The main subcellular localizations were presented in the table on the right. Black dots indicate the presence of the protein to the corresponding subcellular localization.

Figure 2

Mitochondria-to-cytosol Bax trafficking. In healthy cells, Bax constantly translocates from the cytosol to the mitochondria. Retrotranslocation of Bax from the mitochondria to the cytosol could be induced by the anti-apoptotic protein Bcl-xL through the formation of a heterocomplex. In apoptotic conditions, Bcl-xL is inhibited by BH3 only sensitizers. Bax translocates to the mitochondria where it becomes activated by BH3 only activators and forms a Bax pore which leads to MOMP and Cytochrome C release. Some elements of the figure were produced using Servier Medical art image bank (www.servier.com).

Figure 3

Subcellular dynamics of the Bcl-2 family of proteins. Schematic representation of the intracellular localizations and dynamics of anti-apoptotic (in red) pro-apoptotic multidomain (in blue) and BH3 only proteins (pink). Non Bcl-2 homologs were presented with dark orange boxes. Continuous and bold lines represent protein translocation in physiological and stress conditions, respectively. Dashed lines represent hypothetical subcellular translocation. trMcl-1, truncated Mcl-1; snMcl-1, shortened nuclear Mcl-1; Bfl-1s, Bfl-1 short isoform. Some elements of the figure were produced using Servier Medical art image bank (www.servier.com).