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'Caspases' are enzymes known as proteases, which play essential roles in apoptosis (cell death) and inflammation. As proteases, they are enzymes that cleave (cut) other proteins. They are called cysteine proteases, because they use a cysteine residue to cut those proteins, and called caspases because the cysteine residue cleaves their substrate proteins at the aspartic acid residue.
Caspases are essential in cells for apoptosis, one of the main types of 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 cytokines. Failure of apoptosis is one of the main contributions to tumour development and autoimmune diseases; this coupled with the unwanted apoptosis that occurs with ischaemia or Alzheimer's disease, has boomed the interest in caspases as potential therapeutic targets since they were discovered in the mid 1990s.

Contents

Types of caspase proteins

The caspase cascade

Discovery of caspases, their functions and roles

See also

References

External links

Types of caspase proteins

Eleven caspases have so far been identified in humans. There are two types of apoptotic caspases: 'initiator (apical) caspases' and 'effector (executioner) caspases'.

★ Initiator caspases (e.g. , , and cleave inactive pro-forms of effector caspases, thereby activating them.

★ Effector caspases (e.g. , , in turn cleave other protein substrates within the cell resulting in the apoptotic process. The initiation of this cascade reaction is regulated by caspase inhibitors.
and , which are overexpressed in some cases of vitiligo and associated autoimmune diseases caused by NALP1 variants,^[1] are not currently classified as initiator or effector in Mesh. This is because they are 'inflammatory' caspases, which in concert with , are involved in cytokine maturation. , is not involved in apoptosis or inflammation, but instead is involved in skin cell development.

The caspase cascade

Caspases are regulated at a post-translational 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 which cause the clustering of the initiator caspases. This allows them to autoactivate, so that they can then proceed to activate the effector caspases.
The caspase cascade can be activated by :

★ Granzyme B (released by cytotoxic T lymphocytes) which is known to activate caspase-3 and -7

★ death receptors (like FAS, TRAIL receptors and TNF receptor) which can activate caspase-8 and -10

★ the apoptosome (regulated by cytochrome c and the Bcl-2 family) which activates caspase-9.
Some of the final targets of caspases include:

★ nuclear lamins

★ ICAD/DFF45 ('I'nhibitor of 'C'aspase 'A'ctivated 'D'Nase or 'D'NA 'F'ragmentation 'F'actor 45)

★ PARP ('P'oly('A'DP) 'R'ibose 'P'olymerase)

★ PAK2 ('P'21-'A'ctivated 'K'inase 2).
The exact contribution that the cleavage of many caspase substrates makes to the biochemistry and morphology of apoptosis is unclear. However, the function of ICAD/DFF45 is to restrain the enzyme 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' seen in apoptotic cells.

Discovery of caspases, their functions and roles

The importance of caspases to apoptosis and programmed cell death was originally established by Robert Horvitz and colleagues who found that the ''ced-3'' gene was required for the cell death that took place during the development of the nematode ''C. elegans''. Horvitz and his colleague Junying Yuan found in 1993 that the protein encoded by the ced-3 gene was a cysteine protease with similar properties to the mammalian interleukin-1-beta converting enzyme (ICE) (now known as caspase 1) which at the time was the only known caspase. Following this discovery, the other mammalian caspases, in addition to caspases in other organisms such as the fruit fly ''Drosophila melanogaster'', were soon identified and characterised. A consortium of researchers in the field decided upon the caspase nomenclature early in 1996, as in many instances a particular caspase had been identified simultaneously by more than one lab, who would each give the protein a different name (e.g. caspase 3 was variously known as CPP32, apopain and Yama). The caspases are numbered in the order in which they were identified, hence the renaming of ICE to caspase 1. Ironically, although ICE was the first mammalian caspase to be characterised due to its similarity to the nematode death gene ced-3, it seems that the principal role for this enzyme is in mediating inflammation rather than in cell death.
For overviews of the discovery of not just caspases but other aspects of apoptosis see articles by Danial and Korsmeyer,^[2] Yuan and Horvitz,^[3] and by Li et al.^[4] in the January 23rd 2004 edition of the journal 'Cell'.

See also

★ Apoptosis

★ pyroptosis

★ Bcl-2

★ Apoptosome

★ paracaspase

★ metacaspase

References

1. Modern genetics, ancient defenses, and potential therapies., , P.K., Gregersen, N Engl J Med., 2007 [PMID 17377166]
2.
Cell Death: Critical Control Points, , N. N., Danial, Cell, 2004

3.
A First Insight into the Molecular Mechanisms of Apoptosis, , J., Yuan, Cell, 2004

4.
Mitochondrial Activation of Apoptosis, , P., Li, Cell, 2004

External links

★ 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.

★ Caspase antibody review

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