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The BCL-2 protein family: opposing activities that mediate cell death

Key Points

  • B-cell lymphoma-2 (BCL-2) family proteins regulate programmed cell death. Some members of the family (such as BCL-2 and BCL-XL) inhibit apoptosis, whereas others (such as BAX and BAK) promote cell death.

  • BH3-only proteins are a distinct and structurally diverse class of proteins that share one motif, the BH3 domain, with BCL-2 family proteins. BH3-only proteins serve as death sentinels and transmit a signal to promote apoptosis to the core BCL-2 family proteins.

  • Various BH3-only proteins interact with specific subsets of anti-apoptotic BCL-2 family members, yielding combinatorial signalling pathways towards apoptosis.

  • Different tissues die prematurely in mice that lack different anti-apoptotic BCL-2 family members. Knockout of certain BH3-only proteins can compensate for the specific tissue defects that are found in mice deficient in BCL-2 family members.

  • At the onset of apoptosis, BAX and BAK undergo conformational changes, cause the outer membrane of the mitochondria to become permeable to various proteins and induce mitochondria to fragment into smaller units.

  • The changes in mitochondria during apoptosis, especially the release of cytochrome c, result in the activation of caspase proteases that orchestrate the efficient dismantling of dying cells.

Abstract

BCL-2 family proteins, which have either pro- or anti-apoptotic activities, have been studied intensively for the past decade owing to their importance in the regulation of apoptosis, tumorigenesis and cellular responses to anti-cancer therapy. They control the point of no return for clonogenic cell survival and thereby affect tumorigenesis and host–pathogen interactions and regulate animal development. Recent structural, phylogenetic and biological analyses, however, suggest the need for some reconsideration of the accepted organizational principles of the family and how the family members interact with one another during programmed cell death. Although these insights into interactions among BCL-2 family proteins reveal how these proteins are regulated, a unifying hypothesis for the mechanisms they use to activate caspases remains elusive.

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Figure 1: Sequence alignment of core BCL-2 family proteins and BH3-only proteins.
Figure 2: Scheme depicting intrinsic and extrinsic pathways of apoptosis.
Figure 3: Space-filling models of the structures of BAX, BCL-W and BCL-XL bound to a BIM BH3-region peptide.
Figure 4: BH3-only protein binding specificity for BCL-2 homologues.
Figure 5: Conformational changes in BCL-2 family members during apoptosis.

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Supplementary information

Supplementary information S1 (movie) | BAX translocation to mitochondria during apoptosis

GFP-BAX imaged in two HeLa cells over a 5-hour time course during staurosporine-induced apoptosis1. BAX changes distribution from the cytosol to mitochondria upstream of caspase activation. (MOV 3994 kb)

Hsu, Y.-T., Wolter, K. & Youle, R. J. Cytosol to membrane redistribution of members of the Bcl-2 family during apoptosis. Proc. Natl Acad. Sci. USA 94, 3668–3672 (1997).

Supplementary information S2 (table) | Subcellular localization of BCL-2 family members (PDF 162 kb)

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Glossary

BH3 motif

The amino-acid sequence LXXXGD, in which X represents any amino acid. This motif is conserved between most core BCL-2 family members and among BH3-only proteins.

TNF receptor family

Cell-surface receptors in the tumour necrosis factor (TNF) family.

Death domain

A protein-interaction module that consists of six α-helices and that is involved in apoptosis and other signalling pathways.

Mitochondrial outer membrane permeabilization

The process by which the outer membrane of mitochondria leaks certain soluble intermembrane space proteins, such as cytochrome c, into the cytoplasm.

Apoptosome

The caspase-9 activation complex that is composed of APAF1 heptamers and that is assembled on binding of APAF1 monomers to cytochrome c.

Inhibitor of apoptosis protein

(IAP). One of a family of proteins that inhibits apoptosis by binding or degrading caspases.

NOD-like receptor

A cytosolic receptor that is homologous to NOD1 and is involved in innate immunity pathways.

E3 ligase

One of a family of proteins that facilitate the transfer of ubiquitin from a donor protein to a specific substrate protein that may signal the target for proteosomal degradation.

ER stress

The accumulation of unfolded or incompletely glycosylated proteins in the endoplasmic reticulum (ER) results in stress that may lead to apoptosis.

Dynein motor complex

A molecular machine that transports cargo along microtubules.

JAK–STAT pathway

The Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway is a signalling pathway that is activated by growth factors and cytokines.

Erythropoiesis

The production of red blood cells.

SLE-like autoimmune disease

A rodent pathology that resembles human systemic lupus erythematosus, which is commonly known as lupus.

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Youle, R., Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9, 47–59 (2008). https://doi.org/10.1038/nrm2308

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