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Apoptosis: controlled demolition at the cellular level

Key Points

  • Apoptosis is characterized by a series of dramatic perturbations to the cellular architecture that contribute not only to cell death, but also prepare cells for removal by phagocytes.

  • Apoptotic cell death is orchestrated by members of the caspase family of cysteine proteases. Caspases target several hundred proteins for restricted proteolysis during this complex process of cell demolition.

  • Although numerous caspase substrates have been linked to specific morphological features of apoptosis, it is likely that many proteins targeted by caspases contribute to death of the cell but have no significant impact on the phenotypic changes that are seen during this process. Because proteins involved in diverse cell functions are cleaved by caspases, it appears that these enzymes use a 'death by a thousand cuts' strategy to ensure that a cell dies. In other words, death by caspase activation probably results from many potentially lethal injuries rather than a single fatal blow.

  • Multiple membrane alterations, most notably the externalization of phosphatidylserine, have been detected on apoptotic cells. These membrane alterations trigger the recognition and engulfment of apoptotic cells by phagocytes.

  • Because apoptotic cells are typically recognized and engulfed by macrophages before leakage of their intracellular contents, apoptosis typically precludes the release of immunostimulatory molecules (called danger signals) that would not normally be present in the extracellular space. Therefore, apart from limiting direct cell damage caused by the release of cytoplasmic contents, one of the main benefits of controlled cell death through apoptosis may be to prevent unwanted immune responses.

Abstract

Apoptosis is characterized by a series of dramatic perturbations to the cellular architecture that contribute not only to cell death, but also prepare cells for removal by phagocytes and prevent unwanted immune responses. Much of what happens during the demolition phase of apoptosis is orchestrated by members of the caspase family of cysteine proteases. These proteases target several hundred proteins for restricted proteolysis in a controlled manner that minimizes damage and disruption to neighbouring cells and avoids the release of immunostimulatory molecules.

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Figure 1: Morphology of apoptosis.
Figure 2: Caspase activation pathways.
Figure 3: Caspases coordinate demolition of key cellular structures and organelles.
Figure 4: Apoptotic cells display ligands that promote their engulfment by phagocytes.

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Acknowledgements

Work in the Martin laboratory is supported by an award from Science Foundation Ireland. We thank P. Delivani for providing the images for Figure 1. We apologize to colleagues for citing reviews instead of primary papers in several places owing to space constraints.

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Correspondence to Seamus J. Martin.

Supplementary information

Supplementary information S1 (movie) | Time-lapse movie of human HeLa cells undergoing apoptosis.

HeLa cells were induced to undergo apoptosis by exposure to 10 μM daunorubicin. Images were taken every minute over 12 hours and were animated at 10 frames/second. The first image represents healthy cells 2 h after treatment. By 4 h, one of the cells begins to round up and detach from the substratum, and this is followed 30 min later by retraction of the neighbouring cell. Dynamic plasma membrane blebbing is then evident in both cells and this continues for several hours. Later, membrane blebs become larger and more stable until, 8.5 hours after the cells were exposed to the pro-apoptotic drug, secondary necrosis begins. During secondary necrosis, cells cease to bleb and large balloon-like swellings can be seen as cells lose plasma membrane integrity and release their contents into the surroundings. Secondary necrosis is a highly undesirable endpoint and this is normally prevented in vivo through removal of apoptotic cells by phagocytes early in the process. (MOV 3995 kb)

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Glossary

Phagocyte

A cell that can engulf and ingest foreign material, such as an apoptotic cell corpse, which then undergoes digestion within lysosomes.

Caspase

One of a family of proteases that have an essential Cys residue in their active site and a requirement for an Asp residue in the substrate cleavage site. Initiator caspases are typically activated in response to particular stimuli, whereas effector caspases are particularly important for the ordered dismantling of vital cellular structures.

Apoptotic body

During apoptosis, cells collapse into small intact fragments that exclude vital dyes. Such fragments are termed apoptotic bodies.

Apoptosome

A large protein complex that comprises cytochrome c and apoptotic protease-activating factor-1 (APAF1), and forms in the presence of ATP or dATP. The apoptosome recruits pro-caspase-9 and results in the allosteric activation of caspase-9.

Granzyme B

A Ser protease contained within the secretory granules of cytotoxic lymphocytes and natural killer cells. Granzyme B cleaves its protein substrates after Asp residues, and can promote caspase activation and apoptosis.

Myosin

One of a family of actin-associated motor proteins that bind to actin fibres by their head domain and use ATP hydrolysis to move along fibres. The tail domain of myosin associates with cargo or other myosin molecules.

Nuclear lamin

One of a family of intermediate filament proteins that form the proteinaceous nuclear lamina structure, which surrounds the nucleus.

ROCK1

An effector of the small GTPase Rho, ROCK1 is a kinase that can phosphorylate myosin light chain, which alters the dynamics of the actin cytoskeleton.

14-3-3 protein

One of a family of small phosphopeptide-binding dimeric proteins that typically act as adaptors or localize components of signalling pathways.

BH3-only protein

A member of a class of pro-apoptotic proteins in the larger B-cell lymphoma-2 (BCL-2) family of proteins. BH3-only proteins share a short (12 amino acid) motif known as the BH3 domain that exhibits homology with a region within BCL-2.

Phosphatidylserine

A membrane phospholipid that is usually localized to the inner leaflet of the plasma membrane, but which is translocated to the outer leaflet during apoptosis.

Scavenger receptor

A type of cell-surface receptor that recognizes modified low-density lipoprotein or other negatively charged macromolecules, and often functions to remove foreign substances or waste materials from the body.

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Taylor, R., Cullen, S. & Martin, S. Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9, 231–241 (2008). https://doi.org/10.1038/nrm2312

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