Caspase 291111 222468984 2008-06-29T14:31:31Z DOI bot 6652755 Citation maintenance. Formatted: title. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. '''Caspases''' are a family of [[cysteine protease]]s, which play essential roles in [[apoptosis]] (programmed cell death), [[necrosis]] and [[inflammation]]. Caspases are essential in [[cell (biology)|cell]]s for [[apoptosis]], one of the main types of programmed cell death in [[developmental biology|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 [[ischemia]] or [[Alzheimer's disease]], has boomed the interest in caspases as potential therapeutic targets since they were discovered in the mid 1990s. == Types of caspase proteins ==<!-- This section is linked from [[Caspase 2]] --> 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. [[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 resulting in 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,<ref>{{cite journal | last = Gregersen | first = P.K. | title = Modern genetics, ancient defenses, and potential therapies | journal = N Engl J Med. | volume = 356 | year = 2007 | month = March 22 | pages = 1263–6 | pmid = 17377166 | accessdate = 2007-03-25 | doi = 10.1056/NEJMe078017 }}[PMID 17377166]</ref> are not currently classified as initiator or effector in [http://www.nlm.nih.gov/cgi/mesh/2007/MB_cgi?mode=&term=Caspases Mesh]. This is because they are '''inflammatory''' caspases, which in concert with [[CASP1]], are involved in cytokine maturation. [[CASP14]], is not involved in apoptosis or inflammation, but instead is involved in skin cell development. == The caspase cascade == Caspases are regulated at a [[translation (genetics)|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 lymphocyte]]s and [[NK cells]]) which is known to activate caspase-3 and -7 * death receptors (like [[FAS ligand|FAS]], [[TRAIL]] receptors and [[Tumor necrosis factor receptor|TNF receptor]]) which can activate caspase-8 and -10 * the [[apoptosome]] (regulated by [[cytochrome c]] and the [[bcl-2|Bcl-2 family]]) which activates [[caspase-9]]. Some of the final targets of caspases include: * nuclear [[lamin]]s * 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]] ''[[Caenorhabditis elegans|C. elegans]]''. Horvitz and his colleague Junying Yuan <ref name="ced-3">{{cite journal | author=Yuan, J et al.| title=The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme| journal=Cell| year=1993| volume=75| pages=641–652| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8242740 | doi=10.1016/0092-8674(93)90485-9}}</ref>found in 1993 that the protein encoded by the ced-3 gene was a 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. 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,<ref>. {{cite journal | last = Danial | first = N. N. | coauthors = Korsmeyer, S. J. | title = Cell Death: Critical Control Points | journal = Cell | volume = 116 | year = 2004 | month = January | pages = 205–219 | url = http://www.cell.com/retrieve/pii/S0092867404000467 | accessdate = 2006-11-06 | doi = 10.1016/S0092-8674(04)00046-7 }} </ref> Yuan and Horvitz,<ref> {{cite journal | last = Yuan | first = J. | coauthors = Horvitz, H. R. | title = A First Insight into the Molecular Mechanisms of Apoptosis | journal = Cell | volume = 116 | year = 2004 | month = January | pages = 53–56 | url = http://www.cell.com/retrieve/pii/S0092867404000285 | accessdate = 2006-11-06 | doi = 10.1016/S0092-8674(04)00028-5 }} </ref> and by Li et al.<ref> {{cite journal | last = Li | first = P. | coauthors = ''et al.'' | title = Mitochondrial Activation of Apoptosis | journal = Cell | volume = 116 | year = 2004 | month = January | pages = 57–59 | url = http://www.cell.com/retrieve/pii/S0092867404000315 | accessdate = 2006-11-06 | doi = 10.1016/S0092-8674(04)00031-5 }} </ref> in the January 23, 2004 edition of the journal '[[Cell (journal)|Cell]]'. However, more recent studies have demonstrated that caspase proteases are also critical regulators of non-death functions, most notably involving the maturation of a wide variety of cell types such as red blood cells and skeletal muscle myoblasts, ==See also== *[[Apoptosis]] *[[pyroptosis]] *[[Bcl-2]] *[[Apoptosome]] *[[paracaspase]] *[[metacaspase]] ==References== <references /> ==External links== * [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Apoptosis.html#The_Mechanisms_of_Apoptosis 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. * [http://www.exactantigen.com/review/Caspase.html Caspase antibody review] * {{MeshName|Caspases}} {{Cysteine proteases}} [[Category:EC 3.4.22]] [[Category:Programmed cell death]] [[Category:Apoptosis]] [[de:Caspasen]] [[es:Caspasa]] [[fr:Caspase]] [[it:Caspasi]] [[nl:Caspase]] [[ja:カスパーゼ]] [[pl:Kaspazy]] [[pt:Caspase]] [[sv:Caspaser]]