View source for Caspase

{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox protein family
| Symbol = Peptidase_C14
| Name = Caspase domain
| image = Caspase 1.png
| width =
| caption = Structure of caspase-1 (CASP1), originally called interleukin-1 beta-converting enzyme (ICE), the first human caspase to be identified.<ref name="Wilson_1994">{{cite journal | vauthors = Wilson KP, Black JA, Thomson JA, Kim EE, Griffith JP, Navia MA, Murcko MA, Chambers SP, Aldape RA, Raybuck SA, et A | title = Structure and mechanism of interleukin-1 beta converting enzyme | journal = Nature | volume = 370 | issue = 6487 | pages = 270–275 | date = July 1994 | pmid = 8035875 | doi = 10.1038/370270a0 | bibcode = 1994Natur.370..270W | s2cid = 4281700 }}</ref>
| Pfam = PF00656
| Pfam_clan = CL0093
| InterPro = IPR002398
| SMART =
| MEROPS = C14
| PROSITE = PS50208
| SCOP = 1ice
| TCDB =
| OPM family =
| OPM protein =
| PDB =
}}

'''Caspases''' ('''c'''ysteine-'''asp'''artic prote'''ases''', '''c'''ysteine '''asp'''art'''ases''' or '''c'''ysteine-dependent '''asp'''artate-directed prote'''ases''') are a family of [[protease]] [[enzyme]]s playing essential roles in [[programmed cell death]]. They are named caspases due to their specific [[cysteine protease]] activity – a cysteine in its active site [[Nucleophilic catalysis|nucleophilically]] attacks and cleaves a target protein only after an [[aspartic acid]] residue. As of 2009, there are 12 confirmed caspases in humans{{refn|group=note|name=Saleh2004|Functional CASP12 is only expressed in some individuals of African descent, while individuals of Asian or Caucasian descent express only a non-functional truncated form.<ref name="Saleh_2004">{{cite journal | vauthors = Saleh M, Vaillancourt JP, Graham RK, Huyck M, Srinivasula SM, Alnemri ES, Steinberg MH, Nolan V, Baldwin CT, Hotchkiss RS, Buchman TG, Zehnbauer BA, Hayden MR, Farrer LA, Roy S, Nicholson DW | title = Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms | journal = Nature | volume = 429 | issue = 6987 | pages = 75–79 | date = May 2004 | pmid = 15129283 | doi = 10.1038/nature02451 | bibcode = 2004Natur.429...75S | doi-access = free }}</ref>}} and 10 in mice, carrying out a variety of cellular functions.

The role of these enzymes in programmed [[cell death]] was first identified in 1993, with their functions in [[apoptosis]] well characterised. This is a form of programmed cell death, occurring widely during development, and throughout life to maintain cell [[homeostasis]]. Activation of caspases ensures that the cellular components are degraded in a controlled manner, carrying out cell death with minimal effect on surrounding [[tissue (biology)|tissue]]s.<ref>{{Cite journal | vauthors = Rathore S, Datta G, Kaur I, Malhotra P, Mohmmed A | title = Disruption of cellular homeostasis induces organelle stress and triggers apoptosis like cell-death pathways in malaria parasite | journal = Cell Death & Disease | volume = 6 | issue = 7 | pages = e1803 | date = 2015-07-02 | pmid = 26136076 | pmc = 4650714 | doi = 10.1038/cddis.2015.142 | language = en }}</ref>

Caspases have other identified roles in programmed cell death such as [[pyroptosis]], [[necroptosis]] and [[PANoptosis]]. These forms of cell death are important for protecting an organism from stress signals and pathogenic attack. Caspases also have a role in inflammation, whereby it directly processes pro-inflammatory [[cytokines]] such as pro-[[Interleukin 1 beta|IL1β]]. These are signalling molecules that allow recruitment of [[immune cells]] to an infected cell or tissue. There are other identified roles of caspases such as cell proliferation, [[tumor]] suppression, cell differentiation, [[neural development]] and [[axon]] guidance and ageing.<ref>{{Cite journal | vauthors = Shalini S, Dorstyn L, Dawar S, Kumar S | title = Old, new and emerging functions of caspases | journal = Cell Death and Differentiation | volume = 22 | issue = 4 | pages = 526–539 | date = 2015-04-01 | pmid = 25526085 | pmc = 4356345 | doi = 10.1038/cdd.2014.216 | language = en | issn = 1350-9047 }}</ref>

''Caspase deficiency'' has been identified as a cause of tumor development. Tumor growth can occur by a combination of factors, including a mutation in a cell cycle gene which removes the restraints on cell growth, combined with mutations in apoptotic proteins such as caspases that would respond by inducing cell death in abnormally growing cells.<ref name="Goodsell_2000">{{Cite journal | vauthors = Goodsell DS | title = The Molecular Perspective: Caspases | journal = The Oncologist | volume = 5 | issue = 5 | pages = 435–436 | date = 2000-10-01 | pmid = 11040280 | doi = 10.1634/theoncologist.5-5-435 | language = en | issn = 1083-7159 | doi-access = free }}</ref> Conversely, over-activation of some caspases such as [[Caspase 3|caspase]]-3 can lead to excessive programmed cell death. This is seen in several [[Neurodegeneration|neurodegenerative]] diseases where neural cells are lost, such as [[Alzheimer's disease]].<ref name="Goodsell_2000" /> Caspases involved with processing inflammatory signals are also implicated in disease. Insufficient activation of these caspases can increase an organism's susceptibility to infection, as an appropriate immune response may not be activated.<ref name="Goodsell_2000" /> The integral role caspases play in cell death and disease has led to research on using caspases as a drug target. For example, inflammatory caspase-1 has been implicated in causing [[autoimmune diseases]]; drugs blocking the activation of Caspase-1 have been used to improve the health of patients. Additionally, scientists have used caspases as cancer therapy to kill unwanted cells in tumors.<ref>{{Cite journal | vauthors = McIlwain DR, Berger T, Mak TW | title = Caspase Functions in Cell Death and Disease | journal = Cold Spring Harbor Perspectives in Biology | volume = 5 | issue = 4 | article-number = a008656 | date = 2013-04-01 | pmid = 23545416 | pmc = 3683896 | doi = 10.1101/cshperspect.a008656 | language = en | issn = 1943-0264 }}</ref>

== Functional classification of caspases ==
Most caspases play a role in programmed cell death. These are summarized in the table below. The enzymes are sub classified into three types: Initiator, Executioner and Inflammatory.<ref name="Galluzzi_2016">{{cite journal | vauthors = Galluzzi L, López-Soto A, Kumar S, Kroemer G | title = Caspases Connect Cell-Death Signaling to Organismal Homeostasis | journal = Immunity | volume = 44 | issue = 2 | pages = 221–231 | date = 2016-02-16 | pmid = 26885855 | doi = 10.1016/j.immuni.2016.01.020 | language = en | issn = 1074-7613 | doi-access = free }}</ref>

{| class="wikitable" style="margin: 1em auto 1em auto;"
! scope="col" | Programmed Cell Death
! scope="col" | Type of Caspase
! scope="col" | Enzyme
! scope="col" | Organism
|-
! rowspan="7" scope="row" | Apoptosis
| rowspan="4" | Initiator
| [[Caspase 2]]
| human and mouse
|-
| [[Caspase 8]]
| human and mouse
|-
| [[Caspase 9]]
| human and mouse
|-
| [[Caspase 10]]
| human only<ref name="Janicke_2006">{{cite journal | vauthors = Jänicke RU, Sohn D, Totzke G, Schulze-Osthoff K | title = Caspase-10 in Mouse or Not? | journal = Science | location = New York, N.Y. | volume = 312 | issue = 5782 | page = 1874 | date = June 2006 | pmid = 16809511 | doi = 10.1126/science.312.5782.1874a | s2cid = 35202855 }}</ref>
|-
| rowspan="3" | Executioner
| [[Caspase 3]]
| human and mouse
|-
| [[Caspase 6]]
| human and mouse
|-
| [[Caspase 7]]
| human and mouse
|-
! rowspan="6" scope="row" | Pyroptosis
| rowspan="6" | Inflammatory
| [[Caspase 1]]
| human and mouse
|-
| [[Caspase 4]]
| human{{refn|group=note|name=Stowe2015|CASP4 and CASP5 are considered to be the human orthologues of CASP11, which was found in mice and rats but not in humans.<ref name="Stowe_2015">{{cite journal | vauthors = Stowe I, Lee B, Kayagaki N | title = Caspase-11: arming the guards against bacterial infection | journal = Immunological Reviews | volume = 265 | issue = 1 | pages = 75–84 | date = May 2015 | pmid = 25879285 | doi = 10.1111/imr.12292 | s2cid = 22393511 }}</ref>}}
|-
| [[Caspase 5]]
| human{{refn|group=note|name=Stowe2015}}
|-
| [[Caspase 11]]
| mouse{{refn|group=note|name=Stowe2015}}
|-
| [[Caspase 12]]
| mouse and some humans{{refn|group=note|name=Saleh2004}}
|-
| [[Caspase 13]]
| cattle only<ref name="Koenig_2001">{{cite journal | vauthors = Koenig U, Eckhart L, Tschachler E | title = Evidence That Caspase-13 Is Not a Human but a Bovine Gene | journal = Biochemical and Biophysical Research Communications | volume = 285 | issue = 5 | pages = 1150–1154 | date = Aug 2001 | pmid = 11478774 | doi = 10.1006/bbrc.2001.5315 | bibcode = 2001BBRC..285.1150K }}</ref>
|-
! scope="row" | Other roles
| Other
| [[Caspase 14]]
| human and mouse
|}

Note that in addition to apoptosis, caspase-8 is also required for the inhibition of another form of programmed cell death called necroptosis. Caspase-14 plays a role in epithelial cell keratinocyte differentiation and can form an epidermal barrier that protects against dehydration and UVB radiation.<ref name="Denecker_2008">{{cite journal | vauthors = Denecker G, Ovaere P, Vandenabeele P, Declercq W | title = Caspase-14 reveals its secrets | journal = The Journal of Cell Biology | volume = 180 | issue = 3 | pages = 451–458 | date = 2008-02-11 | pmid = 18250198 | pmc = 2234247 | doi = 10.1083/jcb.200709098 | language = en | issn = 0021-9525 | hdl = 1854/LU-394311 }}</ref>

== Activation of caspases ==
Caspases are synthesised as inactive [[zymogen]]s (pro-caspases) that are only activated following an appropriate stimulus. This post-translational level of control allows rapid and tight regulation of the enzyme.<ref>{{cite journal | vauthors = Parrish AB, Freel CD, Kornbluth S | title = Cellular Mechanisms Controlling Caspase Activation and Function | journal = Cold Spring Harbor Perspectives in Biology | volume = 5 | issue = 6 | article-number = a008672 | date = 2013 | pmid = 23732469 | pmc = 3660825 | doi = 10.1101/cshperspect.a008672 }}</ref>

Activation involves dimerization and often oligomerisation of pro-caspases, followed by cleavage into a small subunit and large subunit. The large and small subunit associate with each other to form an active heterodimer caspase. The active enzyme often exists as a heterotetramer in the biological environment, where a pro-caspase dimer is cleaved together to form a heterotetramer.<ref name="Shi_2004" />

=== Dimerisation ===
The activation of initiator caspases and inflammatory caspases is initiated by dimerisation, which is facilitated by binding to [[Signal transducing adaptor protein|adaptor protein]]s via [[protein–protein interaction]] motifs that are collectively referred to as [[death fold]]s. The death folds are located in a structural domain of the caspases known as the pro-domain, which is larger in those caspases that contain death folds than in those that do not. The pro-domain of the intrinsic initiator caspases and the inflammatory caspases contains a single death fold known as [[caspase recruitment domain]] (CARD), while the pro-domain of the extrinsic initiator caspases contains two death folds known as [[death effector domain]]s (DED).<ref name="Lahm_2003">{{cite journal | vauthors = Lahm A, Paradisi A, Green DR, Melino G | title = Death fold domain interaction in apoptosis | journal = Cell Death and Differentiation | volume = 10 | issue = 1 | pages = 10–12 | date = Jan 2003 | pmid = 12655289 | doi = 10.1038/sj.cdd.4401203 | s2cid = 32593733 }}</ref><ref name="Kumar_2007">{{cite journal | vauthors = Kumar S | title = Caspase function in programmed cell death | journal = Cell Death and Differentiation | volume = 14 | issue = 1 | pages = 32–43 | date = Jan 2007 | pmid = 17082813 | doi = 10.1038/sj.cdd.4402060 | doi-access = free | hdl = 2440/45413 | hdl-access = free }}</ref>

''Multiprotein complexes'' often form during caspase activation.<ref name="Shi_2004">{{cite journal | vauthors = Shi Y | title = Caspase Activation | journal = Cell | volume = 117 | issue = 7 | pages = 855–858 | date = 2004-06-25 | pmid = 15210107 | doi = 10.1016/j.cell.2004.06.007 | language = en | issn = 0092-8674 | s2cid = 10129334 | doi-access = free }}</ref> Some activating multiprotein complexes includes:
* The ''[[death-inducing signaling complex]]'' (DISC) during extrinsic apoptosis
* The ''[[apoptosome]]'' during intrinsic apoptosis
* The ''[[inflammasome]]'' during pyroptosis

=== Cleavage ===
Once appropriately dimerised, the Caspases cleave at inter domain linker regions, forming a large and small subunit. This cleavage allows the active-site loops to take up a conformation favourable for enzymatic activity.<ref>{{Cite journal | vauthors = Riedl SJ, Shi Y | title = Molecular mechanisms of caspase regulation during apoptosis | journal = Nature Reviews. Molecular Cell Biology | volume = 5 | issue = 11 | pages = 897–907 | date = Nov 2004 | pmid = 15520809 | doi = 10.1038/nrm1496 | s2cid = 19498556 }}</ref>

''Cleavage of Initiator and Executioner caspases'' occur by different methods outlined in the table below.
* Initiator caspases auto-proteolytically cleave whereas Executioner caspases are cleaved by initiator caspases. This hierarchy allows an amplifying chain reaction or cascade for degrading cellular components, during controlled cell death.

{| class="wikitable"
|-
|Initiator Caspase
Caspase-8
||
[[File:Caspase 8 final.png|thumb|300px|Inititator Pro-caspases have a prodomain that allows recruitment of other pro-caspases, which subsequently dimerise. Both pro-caspase molecules undergo cleavage by autocatalysis. This leads to removal of the prodomain and cleavage of the linker region between the large and small subunit. A heterotetramer is formed]]
 | valign="top" |
[[File:Cas8 pdb.png|thumb|300px|PDB image of caspase 8 (3KJQ) in 'biological assembly'. Two shades of blue used to represent two small sunits, while two shades of purple represent two large subunits]]
|-
| Executioner
Caspase Caspase-3

||
[[File:Caspase 3 final.png|thumb|300px| Executioner caspases constitutively exist as homodimers. The red cuts represent regions where initiator caspases cleave the executioner caspases. The resulting small and large subunit of each Caspase-3 will associate, resulting in a heterotetramer.]]<ref>{{Cite journal | vauthors = Lavrik I, Krueger A, Schmitz I, Baumann S, Weyd H, Krammer PH, Kirchhoff S | title = The active caspase-8 heterotetramer is formed at the CD95 DISC | journal = Cell Death and Differentiation | volume = 10 | issue = 1 | pages = 144–145 | date = 2003-01-01 | pmid = 12655304 | doi = 10.1038/sj.cdd.4401156 | language = en | issn = 1350-9047 | doi-access = free }}</ref>
 ||
[[File:Cas3 pdb.png|thumb|300px|PDB image of Caspase 3 (4QTX) in 'biological assembly'. Two shades of blue used to represent two small sunits, while two shades of purple represent two large subunits]]
|}

== Some roles of caspases ==

=== Apoptosis ===
[[File:Apop1.png|right|thumb|300px|Initiator caspases are activated by intrinsic and extrinsic apoptotic pathways. This leads to the activation of other caspases including executioner caspases that carry out apoptosis by cleaving cellular components.]]
Apoptosis is a form of [[programmed cell death]] where the cell undergoes morphological changes, to minimize its effect on surrounding cells to avoid inducing an immune response. The cell shrinks and condenses - the [[cytoskeleton]] will collapse, and the nuclear envelope disassembles the DNA fragments up. This results in the cell forming self-enclosed bodies called '[[Bleb (cell biology)|blebs]]', to avoid release of cellular components into the [[Extracellular matrix|extracellular]] medium. Additionally, the cell membrane [[phospholipid]] content is altered, which makes the dying cell more susceptible to phagocytic attack and removal.<ref>{{Cite journal | vauthors = Elmore S | title = Apoptosis: A Review of Programmed Cell Death | journal = Toxicologic Pathology | volume = 35 | issue = 4 | pages = 495–516 | date = 2007-06-01 | pmid = 17562483 | pmc = 2117903 | doi = 10.1080/01926230701320337 | language = en | issn = 0192-6233 }}</ref>

''Apoptotic caspases are subcategorised as:''
# ''Initiator Caspases'' ([[Caspase 2]], [[Caspase 8]], [[Caspase 9]], [[Caspase 10]])
# ''Executioner Caspases'' ([[Caspase 3]], [[Caspase 6]] and [[Caspase 7]])
Once initiator caspases are activated, they produce a chain reaction, activating several other executioner caspases. Executioner caspases degrade over 600 cellular components<ref name="Sollberger_2014">{{Cite journal | vauthors = Sollberger G, Strittmatter GE, Garstkiewicz M, Sand J, Beer HD | title = Caspase-1: The inflammasome and beyond | journal = Innate Immunity | volume = 20 | issue = 2 | pages = 115–125 | date = 2014-02-01 | pmid = 23676582 | doi = 10.1177/1753425913484374 | language = en | issn = 1753-4259 | s2cid = 206787156 | url = https://discovery.dundee.ac.uk/en/publications/d53bae44-552f-4d8f-810d-9b8338468e80 | doi-access = free }}</ref> in order to induce the morphological changes for apoptosis.

''Examples of caspase cascade during apoptosis:''
# ''Intrinsic apoptotic pathway:'' During times of cellular stress, mitochondrial ''[[Cytochrome c|cytochrome]]'' c is released into the cytosol. This molecule binds an adaptor protein ([[APAF1|APAF]]-1), which recruits initiator Caspase-9 (via CARD-CARD interactions). This leads to the formation of a Caspase activating multiprotein complex called the ''[[Apoptosome]].'' Once activated, initiator caspases such as Caspase 9 will cleave and activate other executioner caspases. This leads to degradation of cellular components for apoptosis.
# ''Extrinsic apoptotic pathway:''  The caspase cascade is also activated by extracellular ligands, via cell surface Death Receptors. This is done by the formation of a multiprotein Death Inducing Signalling Complex (DISC) that recruits and activates a pro-caspase. For example, the Fas Ligand binds the FasR receptor at the receptor's extracellular surface; this activates the death domains at the cytoplasmic tail of the receptor. The adaptor protein FADD will recruit (by a Death domain-Death domain interaction) pro-Caspase 8 via the DED domain. This FasR, FADD and pro-Caspase 8 form the Death Inducing Signalling Complex (DISC) where ''Caspase-8 is activated.'' This could lead to either downstream activation of the intrinsic pathway by inducing mitochondrial stress, or direct activation of Executioner Caspases (Caspase 3, Caspase 6 and Caspase 7) to degrade cellular components as shown in the adjacent diagram.<ref>{{cite journal | vauthors = Creagh EM | title = Caspase crosstalk: integration of apoptotic and innate immune signalling pathways | journal = Trends in Immunology | volume = 35 | issue = 12 | pages = 631–640 | date = December 2014 | pmid = 25457353 | doi = 10.1016/j.it.2014.10.004 }}</ref>

=== Pyroptosis ===
Pyroptosis is a form of programmed cell death that inherently induces an immune response. It is morphologically distinct from other types of cell death – cells swell up, rupture and release pro-inflammatory cellular contents. This is done in response to a range of stimuli including microbial infections as well as heart attacks (myocardial infarctions).<ref>{{Cite journal | vauthors = Bergsbaken T, Fink SL, Cookson BT | title = Pyroptosis: host cell death and inflammation | journal = Nature Reviews. Microbiology | volume = 7 | issue = 2 | pages = 99–109 | date = Feb 2009 | pmid = 19148178 | pmc = 2910423 | doi = 10.1038/nrmicro2070 }}</ref> Caspase-1, Caspase-4 and Caspase-5 in humans, and Caspase-1 and Caspase-11 in mice play important roles in inducing cell death by pyroptosis. This limits the life and proliferation time of intracellular and extracellular pathogens.{{citation needed|date=February 2021}}

==== Pyroptosis by caspase-1 ====

Caspase-1 activation is mediated by a repertoire of proteins, allowing detection of a range of pathogenic ligands. Some mediators of Caspase-1 activation are: NOD-like Leucine Rich Repeats (NLRs), [[AIM2]]-Like Receptors (ALRs), Pyrin and [[IFI16]].<ref name="Eldridge_2015" />

These proteins allow caspase-1 activation by forming a multiprotein activating complex called Inflammasomes. For example, a NOD Like Leucine Rich Repeat NLRP3 will sense an efflux of potassium ions from the cell. This cellular ion imbalance leads to oligomerisation of NLRP3 molecules to form a multiprotein complex called the [[NLRP3 inflammasome]]. The pro-caspase-1 is brought into close proximity with other pro-caspase molecule in order to dimerise and undergo auto-proteolytic cleavage.<ref name="Eldridge_2015" />

Some pathogenic signals that lead to Pyroptosis by Caspase-1 are listed below:
* ''DNA in the host cytosol'' binds to AIM2-Like Receptors inducing Pyroptosis
* ''Type III secretion system apparatus from bacteria'' bind NOD Like Leucine Rich Repeats receptors called NAIP's (1 in humans and 4 in mice)
''Pyroptosis by Caspase-4 and Caspase-5 in humans and Caspase-11 in mice''

These caspases have the ability to induce direct pyroptosis when [[lipopolysaccharide]] (LPS) molecules (found in the cell wall of gram negative bacteria) are found in the cytoplasm of the host cell. For example, Caspase 4 acts as a receptor and is proteolytically activated, without the need of an inflammasome complex or Caspase-1 activation.<ref name="Eldridge_2015" />

A crucial downstream substrate for pyroptotic caspases is [[Gasdermin D]] (GSDMD)<ref>{{Cite journal | vauthors = He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, Yang ZH, Zhong CQ, Han J | title = Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion | journal = Cell Research | volume = 25 | issue = 12 | pages = 1285–1298 | date = 2015-12-01 | pmid = 26611636 | pmc = 4670995 | doi = 10.1038/cr.2015.139 | language = en | issn = 1001-0602 }}</ref>

=== Role in inflammation ===
Inflammation is a protective attempt by an organism to restore a homeostatic state, following disruption from harmful stimulus, such as tissue damage or bacterial infection.<ref name="Sollberger_2014" />

Caspase-1, Caspase-4, Caspase-5 and Caspase-11 are considered 'Inflammatory Caspases'.<ref name="Galluzzi_2016" />
* ''Caspase-1'' is key in activating pro-inflammatory [[cytokine]]s; these act as signals to immune cells and make the environment favourable for immune cell recruitment to the site of damage. Caspase-1 therefore plays a fundamental role in the [[innate immune system]]. The enzyme is responsible for processing cytokines such as pro-ILβ and pro-IL18, as well as secreting them.<ref name="Eldridge_2015">{{Cite journal | vauthors = Eldridge MJ, Shenoy AR | title = Antimicrobial inflammasomes: unified signalling against diverse bacterial pathogens | journal = Current Opinion in Microbiology | volume = 23 | pages = 32–41 | date = Feb 2015 | pmid = 25461570 | doi = 10.1016/j.mib.2014.10.008 | s2cid = 32160317 }}</ref>
* ''Caspase-4 and -5 in humans, and Caspase-11'' ''in mice'' have a unique role as a receptor, whereby it binds to LPS, a molecule abundant in gram negative bacteria. This can lead to the processing and secretion of IL-1β and IL-18 cytokines by activating Caspase-1; this downstream effect is the same as described above. It also leads to the secretion of another inflammatory cytokine that is not processed. This is called pro-IL1α.<ref name="Eldridge_2015" /> There is also evidence of an inflammatory caspase, caspase-11 aiding cytokine secretion; this is done by inactivating a membrane channel that blocks IL-1β secretion<ref name="Eldridge_2015" />
* Caspases can also induce an inflammatory response on a transcriptional level. There is evidence where it promotes transcription of ''nuclear factor-κB ([[NF-κB]]''), a transcription factor that assists in transcribing inflammatory cytokines such as [[Interferon|IFN]]s, [[Tumor necrosis factors|TNF]], [[Interleukin 6|IL-6]] and [[Interleukin 8|IL-8]]. For example, Caspase-1 activates Caspase-7, which in turn cleaves the [[Poly ADP ribose polymerase|poly (ADP) ribose]] – this activates transcription of NF-κB controlled genes.<ref name="Sollberger_2014" />

== Discovery of caspases ==
[[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]] ''[[Caenorhabditis elegans|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). At the time, ICE was the only known caspase.<ref name="Yuan_1993">{{cite journal | vauthors = Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR | title = The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme | journal = Cell | volume = 75 | issue = 4 | pages = 641–652 | date = Nov 1993 | pmid = 8242740 | doi = 10.1016/0092-8674(93)90485-9 | doi-access = free }}</ref> Other mammalian caspases were subsequently identified, in addition to caspases in organisms such as fruit fly ''[[Drosophila melanogaster]]''.{{cn|date=November 2024}}

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; each would then 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.<ref name="Alnemri ES">{{cite journal | vauthors = Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J | title = Human ICE/CED-3 Protease Nomenclature | journal = Cell | volume = 87 | issue = 2 | page = 171 | date = Oct 1996 | pmid = 8861900 | doi = 10.1016/S0092-8674(00)81334-3 | s2cid = 5345060 | doi-access = free }}</ref> 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.{{cn|date=November 2024}}

== Evolution ==
In animals apoptosis is induced by caspases and in fungi and plants, apoptosis is induced by arginine and lysine-specific caspase-like proteases called metacaspases.  Homology searches revealed a close homology between caspases and the caspase-like proteins of ''Reticulomyxa'' (a unicellular organism). The phylogenetic study indicates that divergence of caspase and metacaspase sequences occurred before the divergence of eukaryotes.<ref>{{Cite journal | vauthors = Klim J, Gładki A, Kucharczyk R, Zielenkiewicz U, Kaczanowski S | title = Ancestral State Reconstruction of the Apoptosis Machinery in the Common Ancestor of Eukaryotes | journal = G3 | location = Bethesda, Md. | volume = 8 | issue = 6 | pages = 2121–2134 | date = 2018-04-27 | pmid = 29703784 | pmc = 5982838 | doi = 10.1534/g3.118.200295 | issn = 2160-1836 }}</ref>

== Detection ==
Detection of executioner caspase activity frequently utilizes the tetrapeptide DEVD, which corresponds to the preferred cleavage motif for [[Caspase 3|caspase‑3]] and [[Caspase 7|caspase‑7]]. DEVD is a short peptide sequence made up of four [[Amino acid|amino acids]]: '''D''' – [[Aspartic acid]] (Asp); '''E''' – [[Glutamic acid]] (Glu); '''V''' – [[Valine]] (Val); '''D''' – [[Aspartic acid]] (Asp).

In [[fluorometric assays]], substrates such as DEVD‑AMC or DEVD‑AFC release a fluorescent moiety upon caspase-mediated cleavage; the fluorescence intensity serves as a direct readout of enzymatic activity. [[Chromogen|Chromogenic]] alternatives like DEVD‑pNA allow similar spectrophotometric measurement.

More sophisticated approaches employ genetically encoded biosensors containing a DEVD linker, which restore fluorescence only after cleavage by active caspases, enabling real-time, live-cell monitoring of [[apoptosis]].<ref name="Selcen_2025">{{cite journal | vauthors = Selcen S, Wieland L, De Oliveira T, Ghadimi M, Conradi LC, Schneider G, Witte L, Wirth M | title = Integrated real-time imaging of executioner caspase dynamics, apoptosis-induced proliferation, and immunogenic cell death using a stable fluorescent reporter platform | journal = Cell Death Discovery | volume = 11 | issue = 1 | article-number = 368 | date = August 2025 | pmid = 40769969 | doi = 10.1038/s41420-025-02662-y }}</ref> A dual-fluorescent reporter system combining a DEVD-containing Zip[[Green fluorescent protein|GFP]] biosensor with constitutive [[mCherry]] expression has been developed. This platform permits dynamic tracking of caspase‑3/‑7 activation and [[apoptosis]] in both 2D and 3D [[Cell culture|culture]] systems, including spheroids and [[Organoid|organoids]], and can be integrated with [[calreticulin]] exposure assays to differentiate immunogenic forms of cell death.<ref name="Selcen_2025" />

==See also==
{{Portal|Biology}}
{{colbegin}}
* [[Apoptosis]]
* [[Apoptosome]]
* [[Bcl-2]]
* [[Emricasan]]
* [[Metacaspase]]
* [[Paracaspase]]
* [[Pyroptosis]]
* [[The Proteolysis Map]]
* [[Programmed cell death]]
* [[Cellular anastasis]]
{{colend}}

==Notes==
{{reflist|group=note}}

==References==
{{Reflist|2}}

==External links==
* {{ELM|CLV_C14_Caspase3-7}}
* [https://web.archive.org/web/20070630103651/http://stke.sciencemag.org/content/vol2007/issue380/images/data/tr1/DC1/Apoptosis_WEHI.mov Apoptosis Video]  Demonstrates a model of a caspase cascade as it occurs in vivo.
* [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Apoptosis.html#The_Mechanisms_of_Apoptosis The Mechanisms of Apoptosis] {{Webarchive|url=https://web.archive.org/web/20180309073759/http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Apoptosis.html#The_Mechanisms_of_Apoptosis |date=2018-03-09 }} 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.
* [https://www.youtube.com/watch?v=4YYboqiol_w Apoptosis & Caspase 7], PMAP-animation
* {{MeshName|Caspases}}
* [https://web.archive.org/web/20110727235334/http://beaker.sanfordburnham.org/?p=1592 Tumors Beware] (from Beaker Blog)

{{Cysteine proteases}}
{{Fas apoptosis signaling pathway}}

[[Category:EC 3.4.22]]
[[Category:Programmed cell death]]
[[Category:Apoptosis]]
[[Category:Proteases]]
[[Category:Caspases]]