BCL2 Family, Mitochondrial Apoptosis, and Beyond

Abstract

Apoptosis is a morphologically and biochemically distinct form of cell death that plays an essential role in development, immune response, and tissue homeostasis. Diminished apoptosis is also considered a hallmark of cancer whereas many cancer treatments induce apoptosis in susceptible cells. Classically, this induction of apoptosis occurs through two major signaling pathways: the extrinsic pathway and the intrinsic pathway. It has been known for 20 years that B-cell lymphoma-2 (BCL2) family proteins control the intrinsic apoptotic pathway by regulating the process of mitochondrial outer membrane permeabilization (MOMP) through protein-protein interactions. Recent studies have elucidated how BCL2 antagonist/killer (BAK) and BCL2-associated X protein (BAX) are activated by BCL2 homology 3 (BH3)-only proteins and how activated BAK and BAX permeabilize MOM, providing increased understanding of how BCL2 family proteins control MOMP. Moreover, both structural and biochemical studies have revealed dual roles for anti-apoptotic BCL2 family proteins in inhibiting BH3-only proteins and restraining activated BAK and BAX. Here, we review recent advances in understanding how BCL2 family proteins control MOMP as well as new nonapoptotic functions for these proteins.