Dismantling the Apoptotic Cell by Caspases


Apoptosis is a programme of cell death that results in dramatic morphological and biochemical changes in the dying cell due to the systematic dismantling of cellular architecture and functional pathways. The proteins that execute the apoptotic programme are a group of proteases termed caspases (cysteine‐dependent aspartate‐specific protease). Caspases proteolytically cleave a host of cellular substrates at aspartate residues, which may render them either functionally inactive or confer novel activities that help to promote cellular demise. Substrates targeted by caspases during the apoptotic programme include proteins involved in maintaining various aspects of cytoskeletal and organelle architecture as well as proteins that function in signalling networks critical for cell function. Following the execution phase of apoptosis, the cellular corpse is packaged in an orderly fashion into membrane‐bound apoptotic bodies that are sensed by phagocytes, which neatly engulf the dead cell without eliciting an immune response.

Key Concepts

  • Apoptotic caspases are cysteine proteases that become activated in response to diverse extracellular and intracellular stimuli and subsequently carry out the cell death programme by systematically cleaving intracellular proteins.
  • A hierarchy of caspase activation exists whereby initiator caspases become activated to cleave and activate effector caspases.
  • The cellular morphological changes associated with apoptosis encompass three stages: release, membrane blebbing and condensation.
  • Caspase‐mediated cleavage of target proteins may produce stable functional effector fragments or unstable fragments that are quickly degraded.
  • Caspases target multiple aspects of the cellular architecture to induce collapse of organelles and the cytoskeleton.
  • Signalling networks that regulate cellular processes critical for cell survival are inactivated by caspases.
  • As the dying cell is dismantled during the apoptotic process, it orchestrates its own disposal by displaying ‘eat me’ signals on its cell surface and releasing ‘find me’ signals to recruit phagocytic cells.

Keywords: initiator caspase; effector caspase; membrane blebbing; nuclear disintegration; cellular condensation; apoptotic bodies

Figure 1. Structure and activation of apoptotic caspases. All caspases are produced as catalytically inactive zymogens or proenzymes containing a prodomain, a large (p20) and a small subunit (p10). The prodomain of the initiator (also known as apical) caspases (2, 8, 9 and 10) is much longer than that of effector caspases 3, 6 and 7. For the initiator caspases, binding to adaptor proteins results in the cleavage of the prodomain and subsequent rearrangement of the large and small subunits to produce a catalytically active heterodimer. Once active, initiator caspases proteolytically cleave effector caspases at distinct aspartate residues, to release the prodomain, large and small subunits. This then allows for the rearrangement of the large and small subunits to form the active heterodimer.
Figure 2. Activation of caspases through intrinsic and extrinsic death pathways. Caspase activation may proceed through either an external (extrinsic) or internal (intrinsic) death pathway, dependent on the stimulus. The intrinsic pathway proceeds through the mitochondria via activation of the pro‐apoptotic Bcl‐2 family members (Bax and Bak), which induce mitochondrial permeabilisation and the release of cytochrome c. Cytoplasmic cytochrome c drives the formation of the apoptosome and activation of initiator caspase 9. Once active, caspase 9 functions to proteolytically cleave and activate the effector caspases 3 and 7, which then go on to cleave numerous intracellular proteins to dismantle the cell. The binding of extracellular ligands to death receptors triggers the formation of a DISC complex resulting in the activation of initiator caspases 8 and/or 10. These caspases can either directly activate caspase 3 or signal through the mitochondria via a Bid‐dependent cleavage event. Truncated Bid (tBid) then activates Bax/Bak which induce mitochondrial permeabilisation, the release of cytochrome c, formation of the apoptosome and the activation of caspases 9 and 3.
Figure 3. Functional outcomes of caspase‐mediated cleavage. Following cleavage of a target protein by effector caspases, there are several probable functional consequences. (a) Caspase‐mediated cleavage of intracellular proteins may result in the production of stable, functionally active effector fragments. These effector fragments may become newly active (as in the case of caspase‐mediated cleavage of ROCK1) or may act to inhibit normal protein function (e.g. caspase‐mediated cleavage of IKB renders the protein resistant to proteosomal degradation and thus allows for sustained inhibition of NFκB, see text for details). (b) On cleavage by caspases many substrates are quickly degraded due to the formation of multiple unstable protein fragments. Cleavage of such substrates quickly depletes the cell of the target protein.
Figure 4. Morphological stages of apoptosis. Caspase‐mediated cleavage of proteins essential for the stability and maintenance of cell–cell contacts, focal adhesions and the actin cytoskeleton results in the loss of cell–cell contacts, the detachment of cells from the substratum and collapse of the cytoskeletal architecture. The cell morphologically appears retracted, as it is ‘released’ from attachment to the surrounding cells and matrix. Caspase‐dependent activation of ROCK1 promotes actomyosin contractility, subsequent fragmentation of the nucleus and Golgi apparatus and membrane blebbing. Lastly, the broken down cellular remnants are tightly packaged and condensed into apoptotic bodies.
Figure 5. Caspases affect cell death by targeting major networks important for cell architecture and viability. Effector caspases dismantle the cell by cleaving key cellular components that function to maintain cell structure and viability. Target proteins include those involved in: (1) signalling networks that regulate cellular processes such as transcription, translation, apoptosis, replication, (2) nuclear structure and function, (3) membrane structure and integrity, (4) cytoskeletal architecture and (5) Golgi structure and function.


Atkin‐Smith GK, Tixeira R, Paone S, et al. (2015) A novel mechanism of generating extracellular vesicles during apoptosis via beads‐on‐a string membrane structure. Nature commun 6: 7439.

Bergeron L, Perez G, Macdonald G, et al. (1998) Defects in regulation of apoptosis in caspase‐2 deficient mice. Genes and Development 12: 1304–1314.

Bratton DL, Fadok VA, Richter DA, et al. (1997) Appearance of phosphatidylserine on apoptotic cells requires calcium‐mediated nonspecific flip‐flop and is enhanced by loss of the aminophospholipid translocase. Journal of Biological Chemistry 272: 26159–26165.

Buendia B, Santa‐Maria A and Courvalin JC (1999) Caspase‐dependent proteolysis of integral and peripheral proteins of nuclear membranes and nuclear pore complex proteins during apoptosis. Journal of Cell Science 112 (part 11): 1743–1753.

Chay KO, Park SS and Mushinski JF (2002) Linkage of caspase‐mediated degradation of paxillin to apoptosis in Ba/F3 murine pro‐B lymphocytes. Journal of Biological Chemistry 277: 14521–14529.

Chekeni FB, Elliott MR, Sandilos JK, et al. (2010) Pannexin 1 channels mediate 'find‐me' signal release and membrane permeability during apoptosis. Nature 467: 863–867.

Crawford ED, Seaman JE, Agard N, et al. (2013) The DegraBase: a database of proteolysis in healthy and apoptotic human cells. Molecular and Cellular Proteomics 12 (3): 813–824.

Coleman ML, Sahai EA, Yeo M, et al. (2001) Membrane blebbing during apoptosis results from caspase‐mediated activation of ROCK I. Nature Cell Biology 3: 339–345.

Dix MM, Simon GM and Cravatt BF (2008) Global mapping of the topography and magnitude of proteolytic events in apoptosis. Cell 134: 679–691.

Elliott MR, Chekeni FB, Trampont PC, et al. (2009) Nucleotides released by apoptotic cells act as a find‐me signal to promote phagocytic clearance. Nature 461: 282–286.

Gohring F, Schwab BL, Nicotera P, Leist M and Fackelmayer FO (1997) The novel SAR‐binding domain of scaffold attachment factor A (SAF‐A) is a target in apoptotic nuclear breakdown. EMBO Journal 16: 7361–7371.

Hakem R, Hakem A, Duncan GS, et al. (1998) Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94: 339–352.

Hanayama R, Tanaka M, Miwa K, et al. (2003) Identification of a factor that links apoptotic cells to phagocytes. Nature 417: 182–187.

Henis‐Korenblit S, Shani G, Sines T, et al. (2002) The caspase‐cleaved DAP5 protein supports internal ribosome entry site‐mediated translation of death proteins. Proceedings of the National Academy of Sciences of the United States of America 99: 5400–5405.

Joselin AP, Schulze‐Osthoff K and Schwerk C (2006) Loss of Acinus inhibits oligonucleosomal DNA fragmentation but not chromatin condensation during apoptosis. Journal of Biological Chemistry 281: 12475–12484.

Kang TB, Ben‐Moshe T, Varfolomeev EE, et al. (2004) Caspase‐8 serves both apoptotic and nonapoptotic roles. Journal of Immunology 173: 2976–2984.

Kuida K, Zheng TS, Na S, et al. (1996) Decreased apoptosis in the brain and premature lethality in CPP32‐deficient mice. Nature 384: 368–372.

Kuida K, Haydar TF, Kuan C‐Y, et al. (1998) Reduced apoptosis and cytochrome c‐mediated caspase activation in mice lacking caspase 9. Cell 94: 325–337.

Kurokawa M and Kornbluth S (2009) Caspases and kinases in a death grip. Cell 138: 838–854.

Lakhani SA, Masud A, Kuida K, et al. (2006) Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science 311: 847–851.

Lane JD, Lucocq J, Pryde J, et al. (2002) Caspase‐mediated cleavage of the stacking protein GRASP65 is required for Golgi fragmentation during apoptosis. Journal of Cell Biology 156: 495–509.

Lauber K, Bohn E, Krober SM, et al. (2003) Apoptotic cells induce migration of phagocytes via caspase‐3‐mediated release of a lipid attraction signal. Cell 113: 717–730.

Leonard JR, Klocke BJ, D'Sa C, et al. (2002) Strain‐dependent neurodevelopmental abnormalities in caspase‐3‐deficient mice. Journal of Neuropathology and Experimental Neurology 61: 673–677.

Luthi AU and Martin SJ (2007) The CASBAH: a searchable database of caspase substrates. Cell Death and Differentiation 14: 641–650.

Mahrus S, Trinidad JC, Barkan DT, et al. (2008) Global sequencing of proteolytic cleavage sites in apoptosis by specific labeling of protein N termini. Cell 134: 866–876.

Marash L and Kimchi A (2005) DAP5 and IRES‐mediated translation during programmed cell death. Cell Death and Differentiation 12: 554–562.

Martin SJ, Finucane DM, Amarante‐Mendes GP, et al. (1996) Phosphatidylserine externalization during CD95‐induced apoptosis of cells and cytoplasts requires ICE/CED‐3 protease activity. Journal of Biological Chemistry 271: 28753–28756.

Miyanishi M, Tada K, Koike M, et al. (2007) Identification of Tim4 as a phosphatidylserine receptor. Nature 450: 435–439.

Moss DK, Betin VM, Malesinski SD and Lane JD (2006) A novel role for microtubules in apoptotic chromatin dynamics and cellular fragmentation. Journal of Cell Science 119 (Pt 11): 2362–2374.

Mukherjee S, Chiu R, Leung SM and Shields D (2007) Fragmentation of the Golgi apparatus: an early apoptotic event independent of the cytoskeleton. Traffic 8: 369–378.

Mukherjee S and Shields D (2009) Nuclear import is required for the pro‐apoptotic function of the Golgi protein p115. Journal of Biological Chemistry 284: 1709–1717.

Oldenborg PA, Zheleznyak A, Fang YF, et al. (2000) Role of CD47 as a marker of self on red blood cells. Science 288: 2051–2054.

Park D, Tosello‐Trampont AC, Elliott MR, et al. (2007) BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450: 430–434.

Prokhorova EA, Zamaraev AV, Kopeina GS, Zhivotovsky B and Lavrik IN (2015) Role of the nucleus in apoptosis; signaling and execution. Cellular and Molecular Life Sciences 72: 4593–4612.

Rudel T and Bokoch GM (1997) Membrane and morphological changes in apoptotic cells regulated by caspase‐mediated activation of PAK2. Science 276: 1571–1574.

Sahara S, Aoto M, Eguchi Y, et al. (1999) Acinus is a caspase‐3‐activated protein required for apoptotic chromatin condensation. Nature 401: 168–173.

Sakamaki K, Inoue T, Asano M, et al. (2002) Ex vivo whole‐embryo culture of caspase‐8‐deficient embryos normalize their aberrant phenotypes in the developing neural tube and heart. Cell Death and Differentiation 9: 1196–1206.

Schwerk C and Schulze‐Osthoff K (2005) Regulation of apoptosis by alternative pre‐mRNA splicing. Molecular Cell 19: 1–13.

Segawa K, Kurata S, Yanagihashi Y, et al. (2014) Caspase‐mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344: 1164–1168.

Suzuki J, Denning DP, Imanishi E, et al. (2013) Xk‐related protein 8 and CED‐8 promote phosphatidylserine exposure in apoptotic cells. Science 341: 403–406.

Timmer JC and Salvesen GS (2007) Caspase substrates. Cell Death and Differentiation 14: 66–72.

Tomiyoshi G, Horita Y, Nishita M, Ohashi K and Mizuno K (2004) Caspase mediated cleavage and activation of LIM‐kinase 1 and its role in apoptotic membrane blebbing. Genes to Cells 9: 591–600.

Varfolomeev EE, Schuchmann M, Luria V, et al. (1998) Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9: 267–276.

Verhoven B, Schlegel RA and Williamson P (1995) Mechanisms of phosphatidylserine exposure, a phagocyte recognition signal, on apoptotic T lymphocytes. Journal of Experimental Medicine 182: 1597–1601.

Widlak P and Garrard WT (2005) Discovery, regulation, and action of the major apoptotic nucleases DFF40/CAD and endonuclease G. Journal of Cellular Biochemistry 94: 1078–1087.

Widmann C, Gibson S and Johnson GL (1998) Caspase‐dependent cleavage of signaling proteins during apoptosis. A turn‐off mechanism for anti‐apoptotic signals. Journal of Biological Chemistry 273: 7141–7147.

Woo M, Hakem R, Soengas MS, et al. (1998) Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes and Development 12: 806–819.

Xu J, Liu D and Songyang Z (2002) The role of Asp‐462 in regulating Akt activity. Journal of Biological Chemistry 277: 35561–35566.

Zandy AJ, Lakhani S, Zheng T, et al. (2005) Role of the executioner caspases during lens development. Journal of Biological Chemistry 280: 30263–30272.

Zheng TS, Hunot S, Kuida K, et al. (1999) Caspase knockouts: matters of life and death. Cell Death and Differentiation 6: 1043–1053.

Further Reading

Atkin‐Smith GK and Poon KH (2016) Disassembly of the dying: mechanisms and functions. Trends in Cell Biology. Epub ahead of print. DOI: 10.1016/j.tcb.2016.08.011.

Croft DR, Coleman ML, Li S, et al. (2005) Actin‐myosin‐based contraction is responsible for apoptotic nuclear disintegration. Journal of Cell Biology 168: 245–255.

Dillon CP, Tummers B, Baran K and Green DR (2016) Developmental checkpoints guarded by regulated necrosis. Cellular and Molecular Life Sciences 73 (11–12): 2125–2136.

Green DR, Oguin TH and Martinez J (2016) The clearance of dying cells: table for two. Cell Death and Differentiation 6: 915–926.

Juo P, Kuo CJ, Yuan J, et al. (1998) Essential requirement for caspase‐8/FLICE in the initiation of the Fas‐induced apoptotic cascade. Current Biology 8: 1001–1008.

Nagata S, Nagase H, Kawane K, Mukae N and Fukuyama H (2003) Degradation of chromosomal DNA during apoptosis. Cell Death and Differentiation 10: 108–116.

Oberst A, Dillon CP, Weinlich R, et al. (2011) Catalytic activity of the caspase‐8‐FLIP(L) complex inhibits RIPK3‐dependent necrosis. Nature 471 (7338): 363–367.

Ranger AM, Malynn BA and Korsmeyer SJ (2001) Mouse models of cell death. Nature Genetics 28: 113–118.

Roux J, Hafner M, Bandara S, et al. (2015) Fractional killing arises from cell‐to‐cell variability in overcoming a caspase activity threshold. Molecular Systems Biology 11: 803.

Segawa K and Nagata S (2015) An apoptotic 'eat me' signal: phosphatidylserine exposure. Trends in Cell Biology 25: 639–650.

Shi J and Wei L (2007) Rho kinase in the regulation of cell death and survival. Archivum Immunologiae et Therapiae Experimentalis 55: 61–75.

Tinel A and Tschopp J (2004) The PIDDosome, a protein complex implicated in activation of caspase‐2 in response to genotoxic stress. Science 304: 843–846.

Vanden Berghe T, Linkermann A, Jouan‐Lanhouet S, Walczak H and Vendenabeele P (2014) Regulated necrosis: the expanding network of non‐apoptotic cell death pathways. Nature Reviews Molecular Cell Biology 15: 135–147.

Wickman GR, Julian L, Mardilovich K, et al. (2013) Blebs produced by actin‐myosin contraction during apoptosis release damage‐associated molecular pattern proteins before secondary necrosis occurs. Cell Death and Differentiation 20: 1293–1305.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Deming, Paula, and Kurokawa, Manabu(Mar 2017) Dismantling the Apoptotic Cell by Caspases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021564.pub2]