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Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins

Nature Reviews Molecular Cell Biology volume 20, pages 175–193 (2019)Cite this article

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Abstract

The loss of vital cells within healthy tissues contributes to the development, progression and treatment outcomes of many human disorders, including neurological and infectious diseases as well as environmental and medical toxicities. Conversely, the abnormal survival and accumulation of damaged or superfluous cells drive prominent human pathologies such as cancers and autoimmune diseases. Apoptosis is an evolutionarily conserved cell death pathway that is responsible for the programmed culling of cells during normal eukaryotic development and maintenance of organismal homeostasis. This pathway is controlled by the BCL-2 family of proteins, which contains both pro-apoptotic and pro-survival members that balance the decision between cellular life and death. Recent insights into the dynamic interactions between BCL-2 family proteins and how they control apoptotic cell death in healthy and diseased cells have uncovered novel opportunities for therapeutic intervention. Importantly, the development of both positive and negative small-molecule modulators of apoptosis is now enabling researchers to translate the discoveries that have been made in the laboratory into clinical practice to positively impact human health.

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Fig. 1: The mitochondrial apoptosis pathway.
Fig. 2: Interactions among BCL-2 family proteins and apoptotic priming.
Fig. 3: Apoptosis and apoptotic priming in physiology.
Fig. 4: Apoptotic dependencies in cancer cells and their responsiveness to therapy.

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Acknowledgements

The authors acknowledge the many researchers who contributed to their understanding of apoptosis and apologize that they could not cite all the relevant research because of space restrictions. The authors thank B. Croker, G. Joshi, A. Presser, J. Spetz, K. Webster and T. Gershon for critical feedback and helpful discussions. The authors gratefully acknowledge funding from the Alex’s Lemonade Stand Foundation for Childhood Cancers Young Investigator Award (K.S.), Andrew McDonough B+ Foundation Childhood Cancer Research Grant (K.S.), Harvard T.H. Chan School of Public Health Dean’s Fund for Scientific Advancement (K.S.), Making Headway Foundation St Baldrick’s Research Grant (K.S.) and NIH/NCI grant R00CA188679 (K.S.).

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Authors and Affiliations

  1. John B. Little Center for Radiation Sciences, Harvard T. H. Chan School of Public Health, Boston, MA, USA

    Rumani Singh & Kristopher Sarosiek

  2. Lab for Systems Pharmacology, Harvard Medical School, Boston, MA, USA

    Rumani Singh, Anthony Letai & Kristopher Sarosiek

  3. Dana-Farber Cancer Institute, Boston, MA, USA

    Anthony Letai

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Glossary

Death receptor

A subgroup of the tumour necrosis factor receptor (TNFR) superfamily that can activate the extrinsic apoptosis pathway via a conserved cytoplasmic signalling platform called the death domain. Prominent members of this family include FAS (also known as Apo1 and CD95), TNFR1 and TRAIL.

Cytochrome c

An essential component of the electron transport chain within mitochondria, where it carries electrons. When released from mitochondria as a result of BCL-2-associated X protein (BAX) and/or BCL 2 antagonist/killer (BAK) activation, cytochrome c has a prominent role in controlling the commitment to apoptosis — it binds to apoptotic protease-activating factor 1 (APAF1) to form an apoptosome, which activates caspases.

Apoptosome

A quaternary protein complex composed of cytoplasmic cytochrome c, apoptotic protease-activating factor 1 (APAF1) and dATP that recruits and activates the normally inactive pro-caspase 9, which then activates effector caspases to prepare the cell for phagocytosis.

Second mitochondria-derived activator of caspases

(SMAC). Also known as DIABLO. A protein that is released from mitochondria during mitochondrial outer membrane permeabilization to bind and inactivate X-linked inhibitor of apoptosis protein (XIAP) to promote caspase activation.

X-linked inhibitor of apoptosis protein

(XIAP). A member of the inhibitor of apoptosis family of proteins that can prevent caspase activation. XIAP binds and inactivates caspases 3, 7 and 9 via its baculovirus IAP repeat BIR2 and BIR3 domains.

cGAS–STING

Cyclic GMP–AMP synthase (cGAS) is a DNA-sensing molecule that activates innate immune responses through production of the second messenger, cyclic GMP–AMP (cGAMP), which then binds to and activates the adaptor protein stimulator of interferon genes (STING). Importantly, cGAS is activated by double-stranded DNA that can be foreign or self.

Damage-associated molecular pattern

(DAMP). A signal that initiates and perpetuates immune activation in response to tissue damage, trauma or ischaemia regardless of whether pathogens are present at the site of injury.

Endoplasmic reticulum stress

(ER stress). A response of the ER to aberrations of protein folding (and other stresses), which is aimed at clearing unfolded proteins and restoring ER homeostasis. In cases when this cannot be accomplished, cellular functions degenerate and often result in apoptosis.

Activation-induced cell death

A programmed cell death process initiated in immune cells (especially T cells) by repeated stimulation of their T cell receptors that helps to maintain peripheral immune tolerance.

Ischaemia–reperfusion injury

A type of tissue damage resulting from initial ischaemia or hypoxia, followed by re-oxygenation, as seen in myocardial infarction, ischaemic stroke and other traumas.

Sertoli cells

Elongated cells of the seminiferous tubules within the testis to which spermatids attach during spermatogenesis for support and nourishment.

Double-negative T cells

(DNTCs). T cells expressing the T cell receptor but lacking CD4, CD8 or natural killer (NK) cell markers.

Cell-cycle checkpoint violation

The failure of a cell to stop at specific checkpoints in the cell cycle when it would normally examine internal and external cues to determine whether to advance with cell division.

Amyloid-β

(Aβ). A peptide produced through the proteolytic cleavage of a transmembrane protein, amyloid precursor protein (APP), by β-secretases and γ-secretases. Accumulation of Aβ in the brain is thought to be an early event in the pathogenesis of Alzheimer disease.

Tau

The major microtubule-associated protein (MAP) of a normal postmitotic and mature neuron. Tau has six molecular isoforms that are generated by alternative splicing and is thought to promote the assembly of tubulin into microtubules. In Alzheimer disease and other tauopathies, tau is hyperphosphorylated and aggregates into neurofibrillary tangles to impair neuronal function.

Neurofibrillary tangles

(NFTs). Aggregates of hyperphosphorylated tau proteins within neurons that cause dysfunction.

4-Hydroxynonenal

(4-HNE). A product of lipid peroxidation that can induce apoptosis.

Ceramide

A lipid that acts as a second messenger in activating apoptosis within the sphingomyelin pathway, which is initiated by the hydrolysis of the plasma membrane phospholipid sphingomyelin.

Presenilin-1

The catalytic subunit of γ-secretase, which is a protease that cleaves a variety of type 1 transmembrane proteins, most notably amyloid precursor protein. Mutations in the PSEN1 gene encoding presenilin 1 are the most common cause of familial Alzheimer disease.

Chorea

A movement disorder that causes involuntary, unpredictable body movements.

TUNEL

(Terminal deoxynucleotidyl transferase dUTP nick end labelling). An assay that detects fragmented DNA, which is one of the hallmarks of apoptotic cell death.

Penumbra

In medicine, the area surrounding the focal point of an ischaemic event.

Excitotoxicity

A process whereby cells in the nervous system are killed by excessive neurotransmitter stimulation.

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Singh, R., Letai, A. & Sarosiek, K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol 20, 175–193 (2019). https://doi.org/10.1038/s41580-018-0089-8

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