View source for Caspase 1

{{Short description|Enzyme found in humans}}
{{Infobox_gene}}
[[File:Caspase-1 Zymogen.jpg|thumb|Caspase-1 Zymogen]]
'''Caspase-1'''/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved [[enzyme]] that [[proteolysis|proteolytically]] cleaves other proteins, such as the [[Protein precursor|precursors]] of the inflammatory [[cytokine]]s [[Interleukin 1 beta|interleukin 1β]] and [[interleukin 18]] as well as the [[pyroptosis]] inducer [[Gasdermin D]], into active mature peptides.<ref name="pmid1574116">{{cite journal | vauthors = Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, Miller DK, Molineaux SM, Weidner JR, Aunins J | display-authors = 6 | title = A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes | journal = Nature | volume = 356 | issue = 6372 | pages = 768–74 | date = April 1992 | pmid = 1574116 | doi = 10.1038/356768a0 | bibcode = 1992Natur.356..768T | s2cid = 4310923 }}</ref><ref name="pmid1373520">{{cite journal | vauthors = Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, Van Ness K, Greenstreet TA, March CJ, Kronheim SR, Druck T, Cannizzaro LA | display-authors = 6 | title = Molecular cloning of the interleukin-1 beta converting enzyme | journal = Science | volume = 256 | issue = 5053 | pages = 97–100 | date = April 1992 | pmid = 1373520 | doi = 10.1126/science.1373520 | bibcode = 1992Sci...256...97C }}</ref><ref name="pmid15190255" /> It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an [[inflammasome]] complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory [[cytokine]]s, [[Interleukin 1 beta|interleukin 1β]] (IL-1β) and [[interleukin 18]] (IL-18) as well as [[pyroptosis]], a programmed lytic [[cell death]] pathway,  through cleavage of Gasdermin D.<ref>{{cite journal | vauthors = Xia S, Zhang Z, Magupalli VG, Pablo JL, Dong Y, Vora SM, Wang L, Fu TM, Jacobson MP, Greka A, Lieberman J, Ruan J, Wu H | display-authors = 6 | title = Gasdermin D pore structure reveals preferential release of mature interleukin-1 | journal = Nature | date = April 2021 | volume = 593 | issue = 7860 | pages = 607–611 | pmid = 33883744 | doi = 10.1038/s41586-021-03478-3 | pmc = 8588876 | bibcode = 2021Natur.593..607X | s2cid = 233351704 }}</ref> The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.<ref name="Jorgensen_2015">{{cite journal | vauthors = Jorgensen I, Miao EA | title = Pyroptotic cell death defends against intracellular pathogens | journal = Immunological Reviews | volume = 265 | issue = 1 | pages = 130–42 | date = May 2015 | pmid = 25879289 | pmc = 4400865 | doi = 10.1111/imr.12287 }}</ref>

== Cellular expression ==
Caspase-1 is evolutionarily conserved in many [[eukaryote]]s of the [[Kingdom (biology)|Kingdom]] [[Animal]]ia. Due to its role in the inflammatory immune response, it is highly expressed in the immune organs such as the [[liver]], [[kidney]], [[spleen]], and [[blood cell|blood]]  ([[neutrophil]]s).<ref>{{cite journal | vauthors = Bakele M, Joos M, Burdi S, Allgaier N, Pöschel S, Fehrenbacher B, Schaller M, Marcos V, Kümmerle-Deschner J, Rieber N, Borregaard N, Yazdi A, Hector A, Hartl D | display-authors = 6 | title = Localization and functionality of the inflammasome in neutrophils | journal = The Journal of Biological Chemistry | volume = 289 | issue = 8 | pages = 5320–9 | date = February 2014 | pmid = 24398679 | pmc = 3931087 | doi = 10.1074/jbc.M113.505636 | doi-access = free }}</ref><ref name="Kumaresan_2016">{{cite journal | vauthors = Kumaresan V, Ravichandran G, Nizam F, Dhayanithi NB, Arasu MV, Al-Dhabi NA, Harikrishnan R, Arockiaraj J | display-authors = 6 | title = Multifunctional murrel caspase 1, 2, 3, 8 and 9: Conservation, uniqueness and their pathogen-induced expression pattern | journal = Fish & Shellfish Immunology | volume = 49 | pages = 493–504 | date = February 2016 | pmid = 26777895 | doi = 10.1016/j.fsi.2016.01.008 | bibcode = 2016FSI....49..493K }}</ref> Following infection, the inflammatory response increases expression of Caspase-1, by a [[positive feedback]] mechanism that amplifies the response.<ref name="Kumaresan_2016" />

== Structure ==

Caspase-1 is produced as a [[zymogen]] that can then be cleaved into 20 kDa (p20) and 10 kDa (p10) subunits that become part of the active enzyme. Active Caspase 1 contains two [[heterodimer]]s of p20 and p10. It contains a catalytic domain with an active site that spans both the p20 and p10 subunits,<ref>{{cite journal | vauthors = Wilson KP, Black JA, Thomson JA, Kim EE, Griffith JP, Navia MA, Murcko MA, Chambers SP, Aldape RA, Raybuck SA | display-authors = 6 | title = Structure and mechanism of interleukin-1 beta converting enzyme | journal = Nature | volume = 370 | issue = 6487 | pages = 270–5 | date = July 1994 | pmid = 8035875 | doi = 10.1038/370270a0 | bibcode = 1994Natur.370..270W | s2cid = 4281700 }}</ref> as well as a noncatalytic Caspase Activation and Recruitment Domain ([[CARD domain|CARD]]) . It interacts with other CARD containing proteins such as Apoptosis-Associated Speck-like Protein Containing a CARD ([[PYCARD|ASC]]) and Nod-Like Receptor ([[NOD-like receptor|NLR]]) Family CARD Domain-Containing Protein 4 ([[NLRC4]]) through CARD-CARD interactions in the formation of inflammasomes.<ref name="pmid15190255">{{cite journal | vauthors = Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM | display-authors = 6 | title = Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf | journal = Nature | volume = 430 | issue = 6996 | pages = 213–8 | date = July 2004 | pmid = 15190255 | doi = 10.1038/nature02664 | bibcode = 2004Natur.430..213M | s2cid = 4317409 }}</ref><ref name="Lu_2016">{{cite journal | vauthors = Lu A, Li Y, Schmidt FI, Yin Q, Chen S, Fu TM, Tong AB, Ploegh HL, Mao Y, Wu H | display-authors = 6 | title = Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism | journal = Nature Structural & Molecular Biology | volume = 23 | issue = 5 | pages = 416–25 | date = May 2016 | pmid = 27043298 | pmc = 4856535 | doi = 10.1038/nsmb.3199 }}</ref>

== Regulation ==
[[File:Subunits of inhibited Caspase 1.jpg|thumb|Inhibited Caspase-1 with 10kDA (Blue) and 20kDA (Green) subunits highlighted]]
[[File:Inflammasome vector.svg|thumb|Example inflammasome structure. The center of the structure is the catalytic domain, outer legs are the sensory domains.]]

=== Activation ===
[[File:CARD-CARD ring.jpg|thumb|CARD-CARD Interaction Mediated Ring Formation]]
Caspase-1, normally in its physiologically inactive zymogen form, autoactivates when it is assembled into the filamentous [[inflammasome]] complex by autoproteolysis into the p10 and p20 subunits.<ref>{{cite journal | vauthors = Elliott JM, Rouge L, Wiesmann C, Scheer JM | title = Crystal structure of procaspase-1 zymogen domain reveals insight into inflammatory caspase autoactivation | journal = The Journal of Biological Chemistry | volume = 284 | issue = 10 | pages = 6546–53 | date = March 2009 | pmid = 19117953 | pmc = 2649088 | doi = 10.1074/jbc.M806121200 | doi-access = free }}</ref><ref name="Humke_2000" /> The inflammasome complex is a ring complex composed of trimers of a signal specific sensor protein such as those of the [[NOD-like receptor|NLR]] family and the AIM-1 (Absent in Melanoma) like receptors, an adaptor protein such as ASC, and a caspase, in this case Caspase-1. In some cases, where the signaling proteins contain their own CARDs, like in [[NLRP1]] and [[NLRC4]], the CARD–CARD interaction is direct, meaning there is no adaptor protein in the complex. There are a variety of sensor and adaptor proteins, the various combinations of which confer the inflammasomes' responses to specific signals. This allows the cell to have varying degrees of inflammatory responses based on the severity of the danger signal received.<ref>{{cite journal | vauthors = Samarani S, Allam O, Sagala P, Aldabah Z, Jenabian MA, Mehraj V, Tremblay C, Routy JP, Amre D, Ahmad A | display-authors = 6 | title = Imbalanced production of IL-18 and its antagonist in human diseases, and its implications for HIV-1 infection | journal = Cytokine | volume = 82 | pages = 38–51 | date = June 2016 | pmid = 26898120 | doi = 10.1016/j.cyto.2016.01.006 | series = Cytokines in inflammation, aging, cancer and obesity }}</ref><ref name="Vince_2016">{{cite journal | vauthors = Vince JE, Silke J | title = The intersection of cell death and inflammasome activation | journal = Cellular and Molecular Life Sciences | volume = 73 | issue = 11–12 | pages = 2349–67 | date = June 2016 | pmid = 27066895 | doi = 10.1007/s00018-016-2205-2 | s2cid = 16281016 | pmc = 11108284 }}</ref>

=== Inhibition ===

CARD only proteins (COPs) as their name implies, are proteins that only contain the non-catalytic CARDs. Owing to the importance of CARD-CARD interactions in inflammasome formation, many COPs are known inhibitors of Caspase activation. For Caspase-1, genes for specific COPs—ICEBERG, COP1 (ICE/Pseudo-ICE), and INCA (Inhibitory Card)—are all found near its locus, and are thus thought to have emerged from gene duplication events and subsequent deletions of the catalytic domains. Though they all interact with the inflammasomes using CARD–CARD interactions, they differ in the way they carry out their inhibitory functions as well as in their effectiveness at doing so.<ref name="Humke_2000">{{cite journal | vauthors = Humke EW, Shriver SK, Starovasnik MA, Fairbrother WJ, Dixit VM | title = ICEBERG: a novel inhibitor of interleukin-1beta generation | journal = Cell | volume = 103 | issue = 1 | pages = 99–111 | date = September 2000 | pmid = 11051551 | doi = 10.1016/S0092-8674(00)00108-2 | s2cid = 15886378 | doi-access = free }}</ref><ref name="Druilhe_2001">{{cite journal | vauthors = Druilhe A, Srinivasula SM, Razmara M, Ahmad M, Alnemri ES | title = Regulation of IL-1beta generation by Pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins | journal = Cell Death and Differentiation | volume = 8 | issue = 6 | pages = 649–57 | date = June 2001 | pmid = 11536016 | doi = 10.1038/sj.cdd.4400881 | doi-access = free }}</ref><ref name="Lamkanfi_2004">{{cite journal | vauthors = Le HT, Harton JA | title = Pyrin- and CARD-only Proteins as Regulators of NLR Functions | journal = Frontiers in Immunology | volume = 4 | pages = 275 | date = September 2013 | pmid = 24062743 | pmc = 3775265 | doi = 10.3389/fimmu.2013.00275 | doi-access = free }}</ref>

For example, ICEBERG nucleates the formation of Caspase-1 filaments and is thus incorporated into the filaments, but lacks the ability to inhibit the activation of inflammasomes. Instead, it is thought to inhibit Caspase-1 activation by interfering with the interaction of Caspase-1 with other important CARD containing proteins.<ref name="Humke_2000" /><ref name="Druilhe_2001" /><ref name="Lamkanfi_2004" />

INCA, on the other hand, directly blocks inflammasome assembly by capping Caspase-1 CARD [[oligomer]]s, thus blocking further polymerization into the inflammasome filaments.<ref name="Druilhe_2001" /><ref name="Lamkanfi_2004" /><ref>{{cite journal | vauthors = Lamkanfi M, Denecker G, Kalai M, D'hondt K, Meeus A, Declercq W, Saelens X, Vandenabeele P | display-authors = 6 | title = INCA, a novel human caspase recruitment domain protein that inhibits interleukin-1beta generation | journal = The Journal of Biological Chemistry | volume = 279 | issue = 50 | pages = 51729–38 | date = December 2004 | pmid = 15383541 | doi = 10.1074/jbc.M407891200 | doi-access = free }}</ref><ref name="Lu_2016"/>

Similarly, some POPs (Pyrin only proteins) are also known to regulate Caspase-1 activation through inhibition of inflammasome activation by binding to and blocking PYD interactions, which also play a role in the formation of the inflammasomes, though the exact mechanisms are not yet well established.<ref name="Lamkanfi_2004"/><ref>{{cite journal | vauthors = Dorfleutner A, Talbott SJ, Bryan NB, Funya KN, Rellick SL, Reed JC, Shi X, Rojanasakul Y, Flynn DC, Stehlik C | display-authors = 6 | title = A Shope Fibroma virus PYRIN-only protein modulates the host immune response | journal = Virus Genes | volume = 35 | issue = 3 | pages = 685–94 | date = December 2007 | pmid = 17676277 | pmc = 4257706 | doi = 10.1007/s11262-007-0141-9 }}</ref>

;Inhibitors
* [[Belnacasan]] (VX-765) <ref name="pmid30254377">{{cite journal | vauthors = Flores J, Noël A, Foveau B, Lynham J, Lecrux C, LeBlanc AC | title = Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer's disease mouse model | journal = Nature Communications | volume = 9 | issue = 1 | pages = 3916 | date = September 2018 | pmid = 30254377 | pmc = 6156230 | doi = 10.1038/s41467-018-06449-x | bibcode = 2018NatCo...9.3916F }}</ref>
* [[Pralnacasan]] (VX-740) <ref name="pmid20229566">{{cite journal | vauthors = Boxer MB, Quinn AM, Shen M, Jadhav A, Leister W, Simeonov A, Auld DS, Thomas CJ | display-authors = 6 | title = A highly potent and selective caspase 1 inhibitor that utilizes a key 3-cyanopropanoic acid moiety | journal = ChemMedChem | volume = 5 | issue = 5 | pages = 730–8 | date = May 2010 | pmid = 20229566 | pmc = 3062473 | doi = 10.1002/cmdc.200900531 }}</ref>

== Function ==

=== Proteolytic cleavage ===

Activated Caspase 1 proteolytically cleaves pro IL-1β and pro IL-18 into their active forms, IL-1β and IL-18. The active cytokines lead to a downstream inflammatory response. It also cleaves Gasdermin D into its active form, which leads to pyroptosis.<ref name="Lu_2016" />

=== Inflammatory response ===

Once matured, the cytokines initiate downstream signaling events to induce a [[Inflammation|proinflammatory]] response as well as to activate the expression of [[Antiviral protein|antiviral]] genes. The speed, specificity and types of response are dependent on the signal received as well as the sensor protein that received it. Signals that can be received by the inflammasomes include [[Double-stranded RNA viruses|viral double stranded RNA]], [[urea]], [[Radical (chemistry)|free radicals]], and other signals associated with cellular danger, even byproducts of other immune response pathways.<ref>{{cite journal | vauthors = Vezzani A, Maroso M, Balosso S, Sanchez MA, Bartfai T | title = IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures | journal = Brain, Behavior, and Immunity | volume = 25 | issue = 7 | pages = 1281–9 | date = October 2011 | pmid = 21473909 | doi = 10.1016/j.bbi.2011.03.018 | s2cid = 3383795 }}</ref>

The mature cytokines themselves do not contain the necessary sorting sequences to enter the [[Endomembrane system|ER–Golgi secretory pathway]], and thus are not excreted from the cell by conventional methods. However, it is theorized that the release of these [[proinflammatory cytokine]]s is not reliant on cellular rupture via [[pyroptosis]], and is in fact, an active process. There exists evidence both for and against this hypothesis. The fact that for many cell types, the cytokines are secreted despite them showing absolutely no signs of pyroptosis, supports this hypothesis.<ref name="Vince_2016"/><ref>{{cite journal | vauthors = Ainscough JS, Gerberick GF, Kimber I, Dearman RJ | title = Interleukin-1β Processing Is Dependent on a Calcium-mediated Interaction with Calmodulin | journal = The Journal of Biological Chemistry | volume = 290 | issue = 52 | pages = 31151–61 | date = December 2015 | pmid = 26559977 | pmc = 4692238 | doi = 10.1074/jbc.M115.680694 | doi-access = free }}</ref> However, some experiments show that Gasdermin D nonfunctional mutants still had normal cleavage of the cytokines but lacked the ability to secrete them, indicating pyroptosis may in fact be necessary for secretion in some way.<ref>{{cite journal | vauthors = He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, Yang ZH, Zhong CQ, Han J | display-authors = 6 | title = Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion | journal = Cell Research | volume = 25 | issue = 12 | pages = 1285–98 | date = December 2015 | pmid = 26611636 | pmc = 4670995 | doi = 10.1038/cr.2015.139 }}</ref>

=== Pyroptosis response ===

Following the inflammatory response, an activated Caspase-1 can induce pyroptosis, a lytic form of cell death, depending on the signal received as well as the specific inflammasome sensor domain protein that received it. Though pyroptosis may or may not be required for the full inflammatory response, the inflammatory response is fully required before pyroptosis can occur.<ref name="Vince_2016"/> In order to induce pyroptosis, Caspase-1 cleaves Gasdermin D into fragments that form pores in the plasma membrane. As a result of osmotic pressure, these pores promote the influx of fluid, resulting in cell lysis and death.<ref>{{cite journal | vauthors = Shi J, Gao W, Shao F | title = Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death | language = English | journal = Trends in Biochemical Sciences | volume = 42 | issue = 4 | pages = 245–254 | date = April 2017 | pmid = 27932073 | doi = 10.1016/j.tibs.2016.10.004 }}</ref>

=== Other roles ===
Caspase-1 has also been shown to induce [[necrosis]] and may also function in various developmental stages. Studies of a similar protein in mice suggest a role in the pathogenesis of [[Huntington's disease]]. [[Alternative splicing]] of the gene results in five transcript variants encoding distinct isoforms.<ref>{{cite web|url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=834|title=Entrez Gene: CASP1 caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)}}</ref> Recent studies implicated caspase-1 in promoting CD4 T-cell death and inflammation by HIV, two signature events that fuel HIV disease progression to AIDS.<ref name="pmid24356306">{{cite journal | vauthors = Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, Hunt PW, Hatano H, Sowinski S, Muñoz-Arias I, Greene WC | display-authors = 6 | title = Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection | journal = Nature | volume = 505 | issue = 7484 | pages = 509–14 | date = January 2014 | pmid = 24356306 | pmc = 4047036 | doi = 10.1038/nature12940 | bibcode = 2014Natur.505..509D }}</ref><ref name="pmid24356113">{{cite journal | vauthors = Monroe KM, Yang Z, Johnson JR, Geng X, Doitsh G, Krogan NJ, Greene WC | title = IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV | journal = Science | volume = 343 | issue = 6169 | pages = 428–32 | date = January 2014 | pmid = 24356113 | pmc = 3976200 | doi = 10.1126/science.1243640 | bibcode = 2014Sci...343..428M }}</ref><ref>{{cite journal | vauthors = Zhang C, Song JW, Huang HH, Fan X, Huang L, Deng JN, Tu B, Wang K, Li J, Zhou MJ, Yang CX, Zhao QW, Yang T, Wang LF, Zhang JY, Xu RN, Jiao YM, Shi M, Shao F, Sékaly RP, Wang FS | display-authors = 6 | title = NLRP3 inflammasome induces CD4+ T cell loss in chronically HIV-1-infected patients | journal = The Journal of Clinical Investigation | volume = 131 | issue = 6 | date = March 2021 | pmid = 33720048 | doi = 10.1172/JCI138861 | pmc = 7954596 | doi-access = free}}</ref> Caspase-1 activity has also been implicated in lysosome acidification following phagocytosis of bacteria<ref>{{cite journal | vauthors = Sokolovska A, Becker CE, Ip WK, Rathinam VA, Brudner M, Paquette N, Tanne A, Vanaja SK, Moore KJ, Fitzgerald KA, Lacy-Hulbert A, Stuart LM | display-authors = 6 | title = Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function | journal = Nature Immunology | volume = 14 | issue = 6 | pages = 543–53 | date = June 2013 | pmid = 23644505 | pmc = 3708594 | doi = 10.1038/ni.2595 }}</ref> and immune complexes.<ref>{{cite journal | vauthors = Monteith AJ, Vincent HA, Kang S, Li P, Claiborne TM, Rajfur Z, Jacobson K, Moorman NJ, Vilen BJ | display-authors = 6 | title = mTORC2 Activity Disrupts Lysosome Acidification in Systemic Lupus Erythematosus by Impairing Caspase-1 Cleavage of Rab39a | journal = Journal of Immunology | volume = 201 | issue = 2 | pages = 371–382 | date = July 2018 | pmid = 29866702 | pmc = 6039264 | doi = 10.4049/jimmunol.1701712 }}</ref>

== See also ==
* [[The Proteolysis Map]] 
* [[Caspase]]
* [[Pyroptosis]] 
* [[Inflammation]]
* [[Inflammasome]]

== References ==
{{Reflist|33em}}

== External links ==
* The [[MEROPS]] online database for peptidases and their inhibitors: [https://archive.today/20121223161347/http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=C14.001 C14.001]

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[[Category:EC 3.4.22]]
[[Category:Caspases]]