Editing Caspase (section)

== 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|last=Elmore|first=Susan|date=2007-06-01|title=Apoptosis: A Review of Programmed Cell Death|journal=Toxicologic Pathology|language=en|volume=35|issue=4|pages=495–516|doi=10.1080/01926230701320337|issn=0192-6233|pmc=2117903|pmid=17562483}}</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=":1">{{Cite journal|last1=Sollberger|first1=Gabriel|last2=Strittmatter|first2=Gerhard E.|last3=Garstkiewicz|first3=Martha|last4=Sand|first4=Jennifer|last5=Beer|first5=Hans-Dietmar|date=2014-02-01|title=Caspase-1: The inflammasome and beyond|journal=Innate Immunity|language=en|volume=20|issue=2|pages=115–125|doi=10.1177/1753425913484374|issn=1753-4259|pmid=23676582|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 apoptopic 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 apoptopic 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 |last=Creagh |first=Emma M. |date=December 2014 |title=Caspase crosstalk: integration of apoptotic and innate immune signalling pathways |journal=Trends in Immunology |volume=35 |issue=12 |pages=631–640 |doi=10.1016/j.it.2014.10.004 |pmid=25457353 }}</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|last1=Bergsbaken|first1=Tessa|last2=Fink|first2=Susan L.|last3=Cookson|first3=Brad T.|title=Pyroptosis: host cell death and inflammation|journal=Nature Reviews Microbiology|volume=7|issue=2|pages=99–109|doi=10.1038/nrmicro2070|pmc=2910423|pmid=19148178|year=2009}}</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=":2" />

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=":2" />

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=":2" />

A crucial downstream substrate for pyroptotic caspases is [[Gasdermin D]] (GSDMD)<ref>{{Cite journal|last1=He|first1=Wan-ting|last2=Wan|first2=Haoqiang|last3=Hu|first3=Lichen|last4=Chen|first4=Pengda|last5=Wang|first5=Xin|last6=Huang|first6=Zhe|last7=Yang|first7=Zhang-Hua|last8=Zhong|first8=Chuan-Qi|last9=Han|first9=Jiahuai|author9-link=Han Jiahuai|date=2015-12-01|title=Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion|journal=Cell Research|language=en|volume=25|issue=12|pages=1285–1298|doi=10.1038/cr.2015.139|issn=1001-0602|pmc=4670995|pmid=26611636}}</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=":1"/>

Caspase-1, Caspase-4, Caspase-5 and Caspase-11 are considered 'Inflammatory Caspases'.<ref name=":5" />
* ''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=":2">{{Cite journal|last1=Eldridge|first1=Matthew JG|last2=Shenoy|first2=Avinash R|title=Antimicrobial inflammasomes: unified signalling against diverse bacterial pathogens|journal=Current Opinion in Microbiology|volume=23|pages=32–41|doi=10.1016/j.mib.2014.10.008|pmid=25461570|year=2015|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=":2"  /> 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=":2" />
* 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=":1"  />