Dismantling the Apoptotic Cell by Caspases

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Dismantling the Apoptotic Cell by Caspases

Paula Deming, University of Vermont, Burlington, Vermont, USA
Manabu Kurokawa, Dartmouth College, Hanover, New Hampshire, USA

Published online: March 2017

DOI: 10.1002/9780470015902.a0021564.pub2

Full Article on Wiley Online Library

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Abstract

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 . Cytoplasmic cytochrome 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 , 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.

Article Title:	Dismantling the Apoptotic Cell by Caspases
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