Unravelling the Bcl-2 Apoptosis Code with a Simple Model System

Primer E very day, a healthy human loses billions of cells by design [1]. Cell death processes, such as apoptosis and other tightly regulated mechanisms that kill old, damaged, or unwanted cells, are critically important for normal embryonic development and for the maintenance of physiological functions in multicellular organisms (and likely in unicellular species as well) [1,2]. Insufficient or excessive cell death underlies most human pathologies, including cancer, autoimmunity, infectious diseases, and degenerative disorders. Thus, it is not surprising that efforts at identifying the factors responsible for cell death and elucidating their detailed mechanisms of action have received considerable research attention. Much of this attention has focused on the Bcl-2 protein family, which has been recognized as the principal regulatory component of the intracellular apoptotic machinery for over two decades [3]. Bcl-2 family proteins can either inhibit or promote apoptosis, largely depending on the number of Bcl-2 homology (BH) domains they share. For example, anti-apoptotic family members, such as Bcl-2 and Bcl-XL, have four BH domains, while pro-apoptotic members such as Bax and Bak contain three, and a third subset, the BH3-only proteins, contains just one. Although there is growing interest in the newly identified roles that both pro-and anti-death Bcl-2 family proteins play in healthy cells—for example, in membrane fission and fusion mechanisms, mitochondrial autophagy, neuronal activity, and cellular energetics [3,4]— most current research is focused on the functions of this family during cell death. Though not universally accepted, it is widely thought that Bcl-2 family proteins regulate commitment to apoptosis primarily through their capacity to control the permeability of the outer mitochondrial membrane (OMM): permeabilization triggers the release of multiple apoptogenic factors into the cytosol and/or leads to mitochondrial dysfunction [5]. Various Bcl-2 family members affect this key event of the apoptotic cascade in different ways, determining their pro-or anti-apoptotic status. The Bcl-2-type proteins inhibit OMM permeabilization, thereby preserving cell viability. In contrast, Bax-type proteins and the diverse group of BH3-only proteins facilitate OMM permeabilization and thus promote cell death. Yet despite intense effort, the question of exactly how different types of Bcl-2 family proteins fulfil these tasks remains actively debated [3,5,6]. Part of the difficulty in resolving the functions of Bcl-2 family proteins is the inherent complexity of the cellular apoptotic network. An additional hurdle is that Bcl-2 protein action likely occurs at membranes, and membrane proteins can be made to reveal their secrets only with difficulty, …