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Caspases, or Cysteine Aspartate-specific Proteases, are enzymes involved in the signal transduction pathways of
apoptosis and inflammation. Caspases are produced in cells as catalytically inactive zymogens which experience proteolytic processing at conserved
aspartic residues. Upon cleavage, they produce 2 subunits, large and small, that dimerize to form the active enzyme. The sequential activation of
caspases plays a central role in the execution-phase of cell apoptosis. There are more than 400 caspases so far identified, and they are divided into
two major classes: effectors and initiators.
Effector Caspases:
Effector caspases, also known as executioner caspases, include
Caspase-3, -6, and -7, and are responsible for cleaving downstream substrates.
Both Caspase-3 and -7 play important roles in apoptosis, where they are activated and enhanced by initiator caspases and are responsible for proteolytic
degradation and the eventual death of a cell.
Initiator Caspases:
Initiator caspases, also known as apical caspases, include
Caspase-1, -2, -4, -5, -8, -9, -10, and -12,
and both interact with and are activated by upstream adaptor molecules through Caspase Activation Recruitment Domains and Death Effector Domains, both of which are protein-protein
interaction domains. Initiator caspases activate downstream effector caspases in a “cascade” during the cell death process of apoptosis.
Apoptosis:
Caspases play a vital role in programmed cell death, apoptosis. Apoptosis is carried out by a “Caspase cascade” that is
activated by two pathways, the Intrinsic (mitochondrial) pathway and the Extrinsic (death receptor) pathway:
The Intrinsic Pathway:
The intrinsic pathway primarily involves mitochondrial outer membrane permeabilization, and its purpose is
to initiate apoptosis upon reception of cellular stress signals (e.g. in the case of damage to DNA). The mitochondrion plays a role as an intracellular death receptor by receiving
a number of proapoptotic signals which trigger oligomerization of proapoptotic proteins. When the stability of a mitochondrial membrane is disturbed, these proteins, namely Bax and
Bak, are released, leading to the activation of initiator caspases to begin the caspase cascade. Bax is a Bcl-2-associated protein, while Bak is a Bcl-2-antagonist killer, and they
cause membrane permeabilization through destabilization of the lipid bilayer. This process leads to the release of cytochrome c into the cytoplasm, a signal for the formation of
Apaf1-containing apoptosomes, which bind and activate initiator procaspase-9. Caspase-9, upon maturation, is still bound to this apoptosome, now a holo-enzyme complex that in turn
activates downstream effector Caspases -3 and -7. The intra-chain cleavage of the effector
Caspase-3 or -7 by initiator Caspase-9 greatly enhances the effectors’ catalytic activity,
leading to cell degredation and death.
The Extrinsic Pathway:
The cell death (extrinsic) pathway is characterized by the elimination of unwanted cells during development.
In this pathway, the ligand for death receptor Fas triggers the Death-Inducing Signaling Complex (DISC) at the cell membrane. This complex is responsible for the recruitment of
initiator Caspase-8, which is consequently cleaved in procaspase form and directly activates
Caspase-3 and other caspases in the cascade. These effector caspases then carry out
cell death. Caspase-8 can also cause apoptosome formation and cytrochrome c release by cleaving a proapoptotic member of the Bcl-2 family, Bid. Effector caspases (Caspase-3,
-6 and -7)
are activated by both the intrinsic and extrinsic pathways, and are responsible for the dismantling of various cell structures by cleaving specific substrate, such as PARP and kinase MST1.
Inflammation:
Outside of involvement with apoptosis, a subset of caspases, including
Caspase-1, -4, and -5 in humans
(Caspase-1 and -12 in mice), are known as inflammatory caspases and are involved in cytokine maturation. They are activated by multiprotein complex inflammasomes,
and are initiator caspases with Caspase Activation Recruitment Domains at the N-terminus. While no specific substrates for human
Caspase-4 or -5 have yet been identified,
two human Caspase-1 substrates have been discovered, proIL-1β and proIL-18. These cytokines are vital participants in inflammation, and have multiple functions. Some of
proIL-18’s functions are to induce adhesion molecule upregulation, activation of natural killer cell activity, and pro-inflammatory cytokines. IL-1β is responsible for
initiating and increasing many of the effects of host response and immunity to tissue damage and microbial invasion, and it is a major inflammation mediator.
Bibliography:
GeneCards: The Human Gene Compendium. Aliases and Descriptions for CASP3 gene.
“Caspase 3, apoptosis-related cysteine peptidase.” Weizmann Institute of Science.
RefSeq. NCBI Gene Summary. “CASP1 caspase, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)
[Homo sapiens].” NCBI, NIH.
Shi, Yigong. “Activation of Initiator Caspases: History, Hypotheses, and Perspectives,” Journal of Cancer
Molecules 1(1): 9-18, 2005.
D’Amelio, M. et. al. “Neuronal capase-3 signaling: not only cell death,” Cell Death and
Differentiation (2010) 17, 1104-1114, 2010.
Los, Marek (MD.) and Henning Walczak. Caspases: Their Role in Cell Death and Cell Survival. Molecular Biology Intelligence Unit, Springer, p. 74. 2003.
Martinon, F. and J. Tschopp. “Inflammatory caspases and inflammasomes: master switches of inflammation,”
Cell Death and Differentiation (2007) 14, 10-22, 2007.
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