Caspase 6 Explained

Caspase-6 is an enzyme that in humans is encoded by the CASP6 gene.^{[1] [2]} CASP6 orthologs^[3] have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts. Caspase-6 has known functions in apoptosis,^[4] early immune response^{[5] [6]} and neurodegeneration in Huntington's and Alzheimer's disease.^[7]

Function

This gene encodes a protein that is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes that undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein is processed by caspases 7, 8 and 10, and is thought to function as a downstream enzyme in the caspase activation cascade. Caspase 6 can also undergo self-processing without other members of the caspase family.^[8] Alternative splicing of this gene results in two transcript variants that encode different isoforms.^[9]

Caspase-6 plays a role in the early immune response via de-repression. It reduces the expression of the immunosuppressant cytokine interleukin-10 and cleaves the macrophage suppressing IRAK-M.

With respect to neurodegeneration, caspase-6 cleaves HTT in Huntington's and APP in Alzheimer's disease. Resulting in both cases in protein aggregation of the fragments.

Interactions

Caspase 6 has been shown to interact with Caspase 8.^{[10] [11] [12]}

See also

• The Proteolysis Map
• Caspase

References

Further reading

• 1995. CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme. J. Biol. Chem.. 269. 49. 30761–4. 7983002. Fernandes-Alnemri T, Litwack G, Alnemri ES. 10.1016/S0021-9258(18)47344-9. free.
• 1996. Cleavage of lamin A by Mch2 alpha but not CPP32: multiple interleukin 1 beta-converting enzyme-related proteases with distinct substrate recognition properties are active in apoptosis. Proc. Natl. Acad. Sci. U.S.A.. 93. 16. 8395–400. 10.1073/pnas.93.16.8395. 38682. 8710882. Takahashi A, Alnemri ES, Lazebnik YA, Fernandes-Alnemri T, Litwack G, Moir RD, Goldman RD, Poirier GG, Kaufmann SH, Earnshaw WC. 1996PNAS...93.8395T. free.
• 1997. Chromosomal mapping of cell death proteases CPP32, MCH2, and MCH3. Genomics. 36. 2. 362–5. 10.1006/geno.1996.0476. 8812467. Bullrich F, Fernandes-Alnemri T, Litwack G, Alnemri ES, Croce CM.
• 1996. The Ced-3/interleukin 1beta converting enzyme-like homolog Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator CPP32. J. Biol. Chem.. 271. 43. 27099–106. 10.1074/jbc.271.43.27099. 8900201. Srinivasula SM, Fernandes-Alnemri T, Zangrilli J, Robertson N, Armstrong RC, Wang L, Trapani JA, Tomaselli KJ, Litwack G, Alnemri ES. free.
• 1997. Molecular ordering of the Fas-apoptotic pathway: The Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases. Proc. Natl. Acad. Sci. U.S.A.. 93. 25. 14486–91. 10.1073/pnas.93.25.14486. 26159. 8962078. Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Litwack G, Alnemri ES. 1996PNAS...9314486S . free.
• 1997. Lamin proteolysis facilitates nuclear events during apoptosis. J. Cell Biol.. 135. 6 Pt 1. 1441–55. 10.1083/jcb.135.6.1441. 2133948. 8978814. Rao L, Perez D, White E.
• 1998. Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease. Science. 277. 5324. 373–6. 10.1126/science.277.5324.373. 9219695. Kim TW, Pettingell WH, Jung YK, Kovacs DM, Tanzi RE. 10.1.1.1025.8052.
• 1997. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis. J. Biol. Chem.. 272. 30. 18542–5. 10.1074/jbc.272.30.18542. 9228018. Srinivasula SM, Ahmad M, Ottilie S, Bullrich F, Banks S, Wang Y, Fernandes-Alnemri T, Croce CM, Litwack G, Tomaselli KJ, Armstrong RC, Alnemri ES. free.
• 1997. Caspase Cleavage of Keratin 18 and Reorganization of Intermediate Filaments during Epithelial Cell Apoptosis. J. Cell Biol.. 138. 6. 1379–94. 10.1083/jcb.138.6.1379. 2132555. 9298992. Caulín C, Salvesen GS, Oshima RG.
• 1998. Caspases Are Activated in a Branched Protease Cascade and Control Distinct Downstream Processes in Fas-induced Apoptosis. J. Exp. Med.. 187. 4. 587–600. 10.1084/jem.187.4.587. 2212161. 9463409. Hirata H, Takahashi A, Kobayashi S, Yonehara S, Sawai H, Okazaki T, Yamamoto K, Sasada M.
• 1998. Caspase-mediated cleavage of the ubiquitin-protein ligase Nedd4 during apoptosis. J. Biol. Chem.. 273. 22. 13524–30. 10.1074/jbc.273.22.13524. 9593687. Harvey KF, Harvey NL, Michael JM, Parasivam G, Waterhouse N, Alnemri ES, Watters D, Kumar S. free.
• 1999. The 72-kDa component of signal recognition particle is cleaved during apoptosis. J. Biol. Chem.. 273. 52. 35362–70. 10.1074/jbc.273.52.35362. 9857079. Utz PJ, Hottelet M, Le TM, Kim SJ, Geiger ME, van Venrooij WJ, Anderson P. free.
• 1999. Caspase-mediated cleavage of DNA topoisomerase I at unconventional sites during apoptosis. J. Biol. Chem.. 274. 7. 4335–40. 10.1074/jbc.274.7.4335. 9933635. Samejima K, Svingen PA, Basi GS, Kottke T, Mesner PW, Stewart L, Durrieu F, Poirier GG, Alnemri ES, Champoux JJ, Kaufmann SH, Earnshaw WC. free.
• 1999. Phosphorylation of presenilin-2 regulates its cleavage by caspases and retards progression of apoptosis. Proc. Natl. Acad. Sci. U.S.A.. 96. 4. 1391–6. 10.1073/pnas.96.4.1391. 15473. 9990034. Walter J, Schindzielorz A, Grünberg J, Haass C. 1999PNAS...96.1391W. free.
• 1999. Identification of caspases that cleave presenilin-1 and presenilin-2. Five presenilin-1 (PS1) mutations do not alter the sensitivity of PS1 to caspases. FEBS Lett.. 445. 1. 149–54. 10.1016/S0014-5793(99)00108-8. 10069390. van de Craen M, de Jonghe C, van den Brande I, Declercq W, van Gassen G, van Criekinge W, Vanderhoeven I, Fiers W, van Broeckhoven C, Hendriks L, Vandenabeele P. 10067/238040151162165141. 31218178. free.
• 1999. Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis. EMBO J.. 18. 8. 2049–56. 10.1093/emboj/18.8.2049. 1171289. 10205159. Xanthoudakis S, Roy S, Rasper D, Hennessey T, Aubin Y, Cassady R, Tawa P, Ruel R, Rosen A, Nicholson DW.

External links

• The MEROPS online database for peptidases and their inhibitors: C14.005

Notes and References

1. Tiso N, Pallavicini A, Muraro T, Zimbello R, Apolloni E, Valle G, Lanfranchi G, Danieli GA . Chromosomal localization of the human genes, CPP32, Mch2, Mch3, and Ich-1, involved in cellular apoptosis . Biochem Biophys Res Commun . 225 . 3 . 983–9 . Oct 1996 . 8780721 . 10.1006/bbrc.1996.1282 . 11577/2461073 . free .
2. Fernandes-Alnemri T, Litwack G, Alnemri ES . Mch2, a new member of the apoptotic Ced-3/Ice cysteine protease gene family . Cancer Res . 55 . 13 . 2737–42 . Aug 1995 . 7796396 .
3. Web site: OrthoMaM phylogenetic marker: CASP6 coding sequence . 2009-12-20 . https://web.archive.org/web/20160303175915/http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000138794_CASP6.xml . 2016-03-03 . dead .
4. Cohen. Gerald M.. 1997-08-15. Caspases: the executioners of apoptosis. Biochemical Journal. en. 326. 1. 1–16. 10.1042/bj3260001. 0264-6021. 9337844. 1218630.
5. Bartel. Alexander. Göhler. André. Hopf. Verena. Breitbach. Katrin. 2017-07-07. Caspase-6 mediates resistance against Burkholderia pseudomallei infection and influences the expression of detrimental cytokines. PLOS ONE. 12. 7. e0180203. 10.1371/journal.pone.0180203. 28686630. 5501493. 2017PLoSO..1280203B. 1932-6203. free.
6. Kobayashi. Hiroshi. Nolan. Anna. Naveed. Bushra. Hoshino. Yoshihiko. Segal. Leopoldo N.. Fujita. Yoko. Rom. William N.. Weiden. Michael D.. 2011-01-01. Neutrophils Activate Alveolar Macrophages by Producing Caspase-6–Mediated Cleavage of IL-1 Receptor-Associated Kinase-M. The Journal of Immunology. en. 186. 1. 403–410. 10.4049/jimmunol.1001906. 0022-1767. 3151149. 21098228.
7. Graham. Rona K.. Ehrnhoefer. Dagmar E.. Hayden. Michael R.. 2011-12-01. Caspase-6 and neurodegeneration. Trends in Neurosciences. en. 34. 12. 646–656. 10.1016/j.tins.2011.09.001. 0166-2236. 22018804. 1603684.
8. Wang XJ, Cao Q, Liu X, Wang KT, Mi W, Zhang Y, Li LF, LeBlanc AC, Su XD . Crystal structures of human caspase 6 reveal a new mechanism for intramolecular cleavage self-activation . EMBO Rep . 11 . 11 . 841–7 . Nov 2010 . 20890311 . 2966951 . 10.1038/embor.2010.141 .
9. Web site: Entrez Gene: CASP6 caspase 6, apoptosis-related cysteine peptidase.
10. Cowling V, Downward J . Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis pathway: absolute requirement for removal of caspase-6 prodomain . Cell Death Differ. . 9 . 10 . 1046–56 . Oct 2002 . 12232792 . 10.1038/sj.cdd.4401065 . free .
11. Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES . Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria . J. Biol. Chem. . 277 . 16 . 13430–7 . Apr 2002 . 11832478 . 10.1074/jbc.M108029200 . free .
12. Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Litwack G, Alnemri ES . Molecular ordering of the Fas-apoptotic pathway: The Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases . . 93 . 25 . 14486–91 . Dec 1996 . 8962078 . 26159 . 10.1073/pnas.93.25.14486 . 1996PNAS...9314486S . free .