Caspase
Encyclopedia
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine protease
s that play essential roles in apoptosis
(programmed cell death), necrosis
, and inflammation
.
Caspases are essential in cell
s for apoptosis
, or programmed cell death, in development
and most other stages of adult life, and have been termed "executioner" proteins for their roles in the cell. Some caspases are also required in the immune system
for the maturation of lymphocytes. Failure of apoptosis is one of the main contributions to tumour development and autoimmune diseases; this, coupled with the unwanted apoptosis that occurs with ischemia
or Alzheimer's disease
, has stimulated interest in caspases as potential therapeutic targets since they were discovered in the mid-1990s.
, twelve caspases have been identified in humans. There are two types of apoptotic caspases: initiator (apical) caspases and effector (executioner) caspases. Initiator caspases (e.g., CASP2, CASP8, CASP9, and CASP10) cleave inactive pro-forms of effector caspases, thereby activating them. Effector caspases (e.g., CASP3, CASP6, CASP7) in turn cleave other protein substrates within the cell, to trigger the apoptotic process. The initiation of this cascade reaction is regulated by caspase inhibitors.
CASP4 and CASP5, which are overexpressed in some cases of vitiligo
and associated autoimmune diseases caused by NALP1 variants, are not currently classified as initiator or effector in MeSH, because they are inflammatory enzymes that, in concert with CASP1, are involved in T-cell maturation. CASP14
is not involved in apoptosis or inflammation, but instead is involved in skin cell development.
level, ensuring that they can be rapidly activated. They are first synthesized as inactive pro-caspases, that consist of a prodomain, a small subunit and a large subunit. Initiator caspases possess a longer prodomain than the effector caspases, whose prodomain is very small. The prodomain of the initiator caspases contain domains such as a CARD domain
(e.g., caspases-2 and -9) or a death effector domain
(DED) (caspases-8 and -10) that enables the caspases to interact with other molecules that regulate their activation. These molecules respond to stimuli that cause the clustering of the initiator caspases. Such clustering allows them to activate automatically, so that they can proceed to activate the effector caspases.
The caspase cascade can be activated by:
Some of the final targets of caspases include:
The role of caspase substrate cleavage in the morphology of apoptosis is not clear. However, ICAD/DFF45 acts to restrain CAD (caspase-activated DNase). The cleavage and inactivation of ICAD/DFF45 by a caspase allows CAD to enter the nucleus and fragment the DNA, causing the characteristic 'DNA ladder' in apoptotic cells.
In 2009, Queensland
researchers announced caspase 1
and 3 in macrophages are regulated by p202 (a double-stranded DNA binding protein) reducing caspase response, and AIM2 (another double-stranded DNA binding protein) increasing caspase activation.http://www.sciencemag.org/cgi/content/short/323/5917/1057
C. elegans
. Horvitz and his colleague Junying Yuan found in 1993 that the protein encoded by the ced-3 gene is cysteine protease with similar properties to the mammal
ian interleukin-1-beta converting enzyme (ICE) (now known as caspase 1), which at the time was the only known caspase. Other mammalian caspases were subsequently identified, in addition to caspases in organisms such as fruit fly Drosophila melanogaster
.
Researchers decided upon the nomenclature of the caspase in 1996. In many instances, a particular caspase had been identified simultaneously by more than one laboratory, who would each give the protein a different name. For example, caspase 3 was variously known as CPP32, apopain and Yama. Caspases, therefore, were numbered in the order in which they were identified. ICE was, therefore, renamed as caspase 1. ICE was the first mammalian caspase to be characterised because of its similarity to the nematode death gene ced-3, but it appears that the principal role of this enzyme is to mediate inflammation rather than cell death.
For the discovery of caspases and other aspects of apoptosis, see articles by Danial and Korsmeyer, Yuan and Horvitz, and by Li et al. in the January 23, 2004 edition of the journal Cell
.
Recent studies have demonstrated that caspase proteases are also regulators of non-death functions, the most notable ones being those involving the maturation of a wide variety of cells such as red blood cell
s and skeletal muscle myoblast
s.
Cysteine protease
Proteases are enzymes that degrade polypeptides. Cysteine proteases have a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic dyad. The first step is deprotonation of a thiol in the enzyme's active site by an adjacent amino acid with a basic side chain, usually a...
s that play essential roles in apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
(programmed cell death), necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
, and inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
.
Caspases are essential in cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s for apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, or programmed cell death, in development
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
and most other stages of adult life, and have been termed "executioner" proteins for their roles in the cell. Some caspases are also required in the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
for the maturation of lymphocytes. Failure of apoptosis is one of the main contributions to tumour development and autoimmune diseases; this, coupled with the unwanted apoptosis that occurs with ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
or Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, has stimulated interest in caspases as potential therapeutic targets since they were discovered in the mid-1990s.
Types of caspase proteins
, twelve caspases have been identified in humans. There are two types of apoptotic caspases: initiator (apical) caspases and effector (executioner) caspases. Initiator caspases (e.g., CASP2, CASP8, CASP9, and CASP10) cleave inactive pro-forms of effector caspases, thereby activating them. Effector caspases (e.g., CASP3, CASP6, CASP7) in turn cleave other protein substrates within the cell, to trigger the apoptotic process. The initiation of this cascade reaction is regulated by caspase inhibitors.
CASP4 and CASP5, which are overexpressed in some cases of vitiligo
Vitiligo
Vitiligo is a condition that causes depigmentation of sections of skin. It occurs when melanocytes, the cells responsible for skin pigmentation, die or are unable to function. The cause of vitiligo is unknown, but research suggests that it may arise from autoimmune, genetic, oxidative stress,...
and associated autoimmune diseases caused by NALP1 variants, are not currently classified as initiator or effector in MeSH, because they are inflammatory enzymes that, in concert with CASP1, are involved in T-cell maturation. CASP14
CASP14
Caspase 14 is an enzyme that in humans is encoded by the CASP14 gene.-External Links:* The MEROPS online database for peptidases and their inhibitors:...
is not involved in apoptosis or inflammation, but instead is involved in skin cell development.
Caspase cascade
Caspases are regulated at a post-translationalTranslation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
level, ensuring that they can be rapidly activated. They are first synthesized as inactive pro-caspases, that consist of a prodomain, a small subunit and a large subunit. Initiator caspases possess a longer prodomain than the effector caspases, whose prodomain is very small. The prodomain of the initiator caspases contain domains such as a CARD domain
CARD domain
Caspase recruitment domains, or Caspase activation and recruitment domains , are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct...
(e.g., caspases-2 and -9) or a death effector domain
Death effector domain
The death-effector domain is a protein interaction domain found to regulate a variety of cellular signalling pathways. The DED domain is found in inactive procaspases and proteins that regulate caspase activation in the apoptosis cascade such as FAS-associating death domain-containing protein...
(DED) (caspases-8 and -10) that enables the caspases to interact with other molecules that regulate their activation. These molecules respond to stimuli that cause the clustering of the initiator caspases. Such clustering allows them to activate automatically, so that they can proceed to activate the effector caspases.
The caspase cascade can be activated by:
- granzyme B (released by cytotoxic T lymphocytes and NK cells), which is known to activate caspase-3 and -7
- death receptors (like FasFAS ligandFas ligand is a type-II transmembrane protein that belongs to the tumor necrosis factor family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.- Structure :Fas ligand or...
, TRAILTRAILIn the field of cell biology, TNF-related apoptosis-inducing ligand , is a protein functioning as a ligand that induces the process of cell death called apoptosis. TRAIL has also been designated CD253 .- Gene :...
receptors and TNF receptorTumor necrosis factor receptorA tumor necrosis factor receptor , or death receptor, is a trimeric cytokine receptor that binds tumor necrosis factors . The receptor cooperates with an adaptor protein , which is important in determining the outcome of the response A tumor necrosis factor receptor (TNFR), or death receptor, is a...
), which can activate caspase-8 and -10 - the apoptosomeApoptosomeThe apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal or external cell death stimulus...
(regulated by cytochrome cCytochrome cThe Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
and the Bcl-2 familyBcl-2Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
), which activates caspase-9Caspase-9Caspase-9 is an initiator caspase, encoded by the CASP9 gene.CASP9 orthologs have been identified in all mammals for which complete genome data are available. Unique orthologs are also present in lizards, lissamphibians, and teleosts....
.
Some of the final targets of caspases include:
- nuclear laminLaminNuclear lamins, also known as Class V intermediate filaments, are fibrous proteins providing structural function and transcriptional regulation in the cell nucleus. Nuclear lamins interact with membrane-associated proteins to form the nuclear lamina on the interior of the nuclear envelope...
s - ICAD/DFF45 (inhibitor of caspase activated DNase or DNA fragmentation factor 45)
- PARP (poly-ADP ribose polymerase)
- PAK2 (P 21-activated kinase 2).
The role of caspase substrate cleavage in the morphology of apoptosis is not clear. However, ICAD/DFF45 acts to restrain CAD (caspase-activated DNase). The cleavage and inactivation of ICAD/DFF45 by a caspase allows CAD to enter the nucleus and fragment the DNA, causing the characteristic 'DNA ladder' in apoptotic cells.
In 2009, Queensland
Queensland
Queensland is a state of Australia, occupying the north-eastern section of the mainland continent. It is bordered by the Northern Territory, South Australia and New South Wales to the west, south-west and south respectively. To the east, Queensland is bordered by the Coral Sea and Pacific Ocean...
researchers announced caspase 1
Caspase 1
Caspase 1 is an enzyme that proteolytically cleaves other proteins, such as the precursor forms of the inflammatory cytokines interleukin 1-β and interleukin 18, into active mature peptides...
and 3 in macrophages are regulated by p202 (a double-stranded DNA binding protein) reducing caspase response, and AIM2 (another double-stranded DNA binding protein) increasing caspase activation.http://www.sciencemag.org/cgi/content/short/323/5917/1057
Discovery of caspases, functions
Robert Horvitz initially established the importance of caspases in apoptosis and found that the ced-3 gene is required for the cell death that took place during the development of the nematodeNematode
The nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode...
C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
. Horvitz and his colleague Junying Yuan found in 1993 that the protein encoded by the ced-3 gene is cysteine protease with similar properties to the mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian interleukin-1-beta converting enzyme (ICE) (now known as caspase 1), which at the time was the only known caspase. Other mammalian caspases were subsequently identified, in addition to caspases in organisms such as fruit fly Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
.
Researchers decided upon the nomenclature of the caspase in 1996. In many instances, a particular caspase had been identified simultaneously by more than one laboratory, who would each give the protein a different name. For example, caspase 3 was variously known as CPP32, apopain and Yama. Caspases, therefore, were numbered in the order in which they were identified. ICE was, therefore, renamed as caspase 1. ICE was the first mammalian caspase to be characterised because of its similarity to the nematode death gene ced-3, but it appears that the principal role of this enzyme is to mediate inflammation rather than cell death.
For the discovery of caspases and other aspects of apoptosis, see articles by Danial and Korsmeyer, Yuan and Horvitz, and by Li et al. in the January 23, 2004 edition of the journal Cell
Cell (journal)
Cell is a peer-reviewed scientific journal publishing research papers across a broad range of disciplines within the life sciences. Areas covered include molecular biology, cell biology, systems biology, stem cells, developmental biology, genetics and genomics, proteomics, cancer research,...
.
Recent studies have demonstrated that caspase proteases are also regulators of non-death functions, the most notable ones being those involving the maturation of a wide variety of cells such as red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s and skeletal muscle myoblast
Myoblast
A myoblast is a type of embryonic progenitor cell that gives rise to muscle cells .The muscle cells can be skeletal muscle, smooth muscle, and cardiac muscle....
s.
See also
- apoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
- apoptosomeApoptosomeThe apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal or external cell death stimulus...
- bcl-2Bcl-2Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
- metacaspaseMetacaspaseMetacaspases are related to caspases and paracaspase. The metacaspases are Arginine/Lysine-specific, in contrast to caspases, which are Aspartate-specific...
- paracaspaseParacaspaseParacaspases are related to caspases present in animals and slime mold, in contrast to metacaspases, which are present in plants, fungi, and "protists"....
- pyroptosisPyroptosisPyroptosis is a form of programmed cell death associated with antimicrobial responses during inflammation. In contrast to apoptosis, pyroptosis requires the function of caspase-1, and has been studied in the context of salmonella-infected macrophages....
- The Proteolysis MapThe Proteolysis MapThe Proteolysis MAP is an integrated web resource focused on proteases.-Rationale:PMAP is to aid the protease researchers in reasoning about proteolytic networks and metabolic pathways.-History and funding:...
External links
- Apoptosis Video Demonstrates a model of a caspase cascade as it occurs in vivo.
- The Mechanisms of Apoptosis Kimball's Biology Pages. Simple explanation of the mechanisms of apoptosis triggered by internal signals (bcl-2), along the caspase-9, caspase-3 and caspase-7 pathway; and by external signals (FAS and TNF), along the caspase 8 pathway. Accessed 25 March 2007.
- Apoptosis & Caspase 7, PMAP-animation
- Tumors Beware (from Beaker Blog)