Structure of interleukin-1 beta-converting enzyme.
Caspases (cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases) are a family of cysteine proteases that play essential roles in apoptosis (programmed cell death), necrosis, and inflammation.
Caspases are essential in cells 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.
Types of caspase proteins
As of November 2009[update], 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.
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 caspase-9) or a death effector domain (DED) (caspases-8 and caspase-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 core interaction of caspases may be regarded as a positive feedback.
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 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 (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 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.
Discovery of caspases, functions
H. 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 nematode 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 mammalian 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.
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 cells and skeletal muscle myoblasts.
- The Proteolysis Map
- Programmed cell death
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- HUGO Gene Nomenclature Committee
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- NIH Medical Subject Headings
- Lopez-Caamal, Fernando; Middleton, Richard H.; Huber, Heinrich (February 2014). "Equilibria and stability of a class of positive feedback loops". Journal of Mathematical Biology: 609–645. doi:10.1007/s00285-013-0644-z.
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- Eukaryotic Linear Motif resource motif class CLV_C14_Caspase3-7
- 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
- Caspases at the US National Library of Medicine Medical Subject Headings (MeSH)
- Tumors Beware (from Beaker Blog)