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Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy

Nature Reviews Molecular Cell Biology volume 15, pages 49–63 (2014)Cite this article

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Key Points

  • The BCL-2 protein family principally determines whether a cell commits to apoptosis and hence has crucial roles in development, tissue homeostasis and immunity. Consequently, alteration of this control can either promote cancer and autoimmune diseases (too little apoptosis) or augment ischaemic conditions and contribute to degenerative disorders (too much apoptosis).

  • The life-or-death decision for a cell is mainly determined by the interactions between three factions of the BCL-2 family: namely, the pro-survival subfamily (for example, BCL-2, BCL-XL and MCL1) and two pro-apoptotic factions, the BH3-only proteins (for example, BIM, PUMA and BID), which convey various cytotoxic signals, and the death effectors BAX and BAK, which can convert into homo-oligomers that perforate the mitochondrial outer membrane, triggering the proteolytic cascade that demolishes the cell.

  • Biochemical and structural studies have shown that the cardinal interaction within the family is the engagement of a groove on the surface of the pro-survival family members, and of BAX and BAK, by the BH3 domain of a pro-apoptotic family member.

  • Insights have recently emerged into how BAX and BAK convert from inert globular monomers into the lethal oligomers that permeabilize the mitochondrial outer membrane. They can be activated by the binding of certain BH3 domains (particularly those of BIM and BID) to their canonical surface groove, and possibly also to a less defined rear site on BAX. The groove binding provokes BAX and BAK to undergo remarkable structural rearrangements that include release of their own BH3 domain, which can then engage the surface groove of another BAX or BAK molecule to form the 'symmetric dimers' that nucleate the larger oligomers.

  • Collectively, the manipulation of BCL-2 family genes in mice indicates that all mammalian cells are poised to commit suicide unless protected by one or more of the pro-survival family members; that nearly all cytotoxic signals, including those used in chemotherapy, are mediated through the activation of one or more BH3-only proteins; and that the activation of either BAX or BAK is necessary and sufficient for mitochondrial pathway apoptosis.

  • Novel anticancer drugs, termed 'BH3 mimetics', which engage the groove of certain pro-survival family members in a manner that is similar to that of the BH3-only proteins, have shown promise in preclinical studies and early clinical trials, particularly in patients with lymphoid malignancies, such as chronic lymphocytic leukaemia. The best characterized are navitoclax (ABT-263), which targets BCL-2, BCL-XL and BCL-W, and the new BCL-2-specific ABT-199. Their combination with other anticancer agents is likely to extend their efficacy to a wider range of malignancies.

Abstract

The BCL-2 protein family determines the commitment of cells to apoptosis, an ancient cell suicide programme that is essential for development, tissue homeostasis and immunity. Too little apoptosis can promote cancer and autoimmune diseases; too much apoptosis can augment ischaemic conditions and drive neurodegeneration. We discuss the biochemical, structural and genetic studies that have clarified how the interplay between members of the BCL-2 family on mitochondria sets the apoptotic threshold. These mechanistic insights into the functions of the BCL-2 family are illuminating the physiological control of apoptosis, the pathological consequences of its dysregulation and the promising search for novel cancer therapies that target the BCL-2 family.

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Figure 1: The mitochondrial and death receptor-mediated pathways to apoptosis.
Figure 2: The structure of BCL-2 family proteins and the selectivity in their interactions.
Figure 3: Direct activation of BAX by BH3-only proteins.
Figure 4: Model for the activation and oligomerization of BAX and BAK.
Figure 5: BH3 mimetics binding to the hydrophobic groove of their pro-survival BCL-2 family target proteins.

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Acknowledgements

P.E.C and G.L contributed equally to this work. The authors thank their colleagues at the Walter and Eliza Hall Institute of Medical Research (WEHI), particularly S. Cory, P. Colman, P. Bouillet, D. Huang, R. Kluck, G. Dewson and D. Westphal, for many stimulating discussions on the issues addressed here, and S. Cory and P. Colman for comments on the manuscript. Their research is supported chiefly by program grant 1016701 and project grants 1025201 and 1025138 from the Australian National Health and Research Council, Australian Research Council (ARC) fellowship FT0992105, funds from the Cancer Council of Victoria and a Center (7417) established by the Leukemia and Lymphoma Society, as well as operational infrastructure grants from the Australian Government (IRISS) and the Victorian State Government (OIS).

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Author notes

  1. Peter E. Czabotar and Guillaume Lessene: These authors contributed equally to this work.

Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, 1G Royal Parade, Parkville, 3052, Victoria, Australia

    Peter E. Czabotar, Guillaume Lessene, Andreas Strasser & Jerry M. Adams

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  1. Peter E. Czabotar
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  3. Andreas Strasser
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Correspondence to Andreas Strasser or Jerry M. Adams.

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Competing interests

The authors had a collaboration with Genentech and Abbott Laboratories (now AbbVie) for cancer drug development.

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Glossary

Sertoli cells

Cells that nourish developing sperm cells through the stages of spermatogenesis.

'Eat me' signals

Surface markers on apoptotic cells, such as phosphatidylserine, that facilitate their recognition and phagocytosis by healthy cells.

Necroptosis

A programmed form of necrosis regulated by receptor-interacting Ser/Thr protein (RIP) kinases.

Activator BH3-only proteins

BH3-only proteins, such as BIM and the truncated form of BID (tBID) that can directly bind and activate BAX or BAK.

Sensitizer BH3-only proteins

BH3-only proteins, such as BAD, that can activate BAX or BAK only indirectly by neutralizing pro-survival BCL-2 family members, thereby preventing them from restraining BAX or BAK.

Staple

A hydrocarbon bridge introduced into a peptide that links amino acids four or seven residues apart to maintain the peptide in a helical conformation, which is thought to convey higher affinity for its target, as well as greater stability and perhaps cell penetration.

Mitochondrial fission and fusion

Mitochondria divide by fission but also continually fuse into tubular networks; thus, their structure is dynamic.

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Czabotar, P., Lessene, G., Strasser, A. et al. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15, 49–63 (2014). https://doi.org/10.1038/nrm3722

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