Caspase-6 is an enzyme that in humans is encoded by the CASP6 gene.[5][6] CASP6 orthologs[7] 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,[8] early immune response[9][10] and neurodegeneration in Huntington's and Alzheimer's disease.[11]
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.[8] 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.[12] Alternative splicing of this gene results in two transcript variants that encode different isoforms.[13]
Caspase-6 plays a role in the early immune response via de-repression. It reduces the expression of the immunosuppressant cytokine interleukin-10[9] and cleaves the macrophage suppressing IRAK-M.[10]
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.[11]
Interactions
Caspase 6 has been shown to interact with Caspase 8.[14][15][16]
See also
References
- GRCh38: Ensembl release 89: ENSG00000138794 – Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000027997 – Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- Tiso N, Pallavicini A, Muraro T, Zimbello R, Apolloni E, Valle G, et al. (Oct 1996). "Chromosomal localization of the human genes, CPP32, Mch2, Mch3, and Ich-1, involved in cellular apoptosis". Biochemical and Biophysical Research Communications. 225 (3): 983–989. doi:10.1006/bbrc.1996.1282. hdl:11577/2461073. PMID 8780721.
- Fernandes-Alnemri T, Litwack G, Alnemri ES (Aug 1995). "Mch2, a new member of the apoptotic Ced-3/Ice cysteine protease gene family". Cancer Research. 55 (13): 2737–2742. PMID 7796396.
- "OrthoMaM phylogenetic marker: CASP6 coding sequence". Archived from the original on 2016-03-03. Retrieved 2009-12-20.
- Cohen GM (August 1997). "Caspases: the executioners of apoptosis". The Biochemical Journal. 326 ( Pt 1) (Pt 1): 1–16. doi:10.1042/bj3260001. PMC 1218630. PMID 9337844.
- Bartel A, Göhler A, Hopf V, Breitbach K (2017-07-07). "Caspase-6 mediates resistance against Burkholderia pseudomallei infection and influences the expression of detrimental cytokines". PLOS ONE. 12 (7) e0180203. Bibcode:2017PLoSO..1280203B. doi:10.1371/journal.pone.0180203. PMC 5501493. PMID 28686630.
- Kobayashi H, Nolan A, Naveed B, Hoshino Y, Segal LN, Fujita Y, et al. (January 2011). "Neutrophils activate alveolar macrophages by producing caspase-6-mediated cleavage of IL-1 receptor-associated kinase-M". Journal of Immunology. 186 (1): 403–410. doi:10.4049/jimmunol.1001906. PMC 3151149. PMID 21098228.
- Graham RK, Ehrnhoefer DE, Hayden MR (December 2011). "Caspase-6 and neurodegeneration". Trends in Neurosciences. 34 (12): 646–656. doi:10.1016/j.tins.2011.09.001. PMID 22018804. S2CID 1603684.
- Wang XJ, Cao Q, Liu X, Wang KT, Mi W, Zhang Y, et al. (Nov 2010). "Crystal structures of human caspase 6 reveal a new mechanism for intramolecular cleavage self-activation". EMBO Reports. 11 (11): 841–847. doi:10.1038/embor.2010.141. PMC 2966951. PMID 20890311.
- "Entrez Gene: CASP6 caspase 6, apoptosis-related cysteine peptidase".
- Cowling V, Downward J (Oct 2002). "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 and Differentiation. 9 (10): 1046–1056. doi:10.1038/sj.cdd.4401065. PMID 12232792.
- Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES (Apr 2002). "Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria". The Journal of Biological Chemistry. 277 (16): 13430–13437. doi:10.1074/jbc.M108029200. PMID 11832478.
- Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Litwack G, Alnemri ES (Dec 1996). "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". Proceedings of the National Academy of Sciences of the United States of America. 93 (25): 14486–14491. Bibcode:1996PNAS...9314486S. doi:10.1073/pnas.93.25.14486. PMC 26159. PMID 8962078.
Further reading
- Fernandes-Alnemri T, Litwack G, Alnemri ES (1995). "CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme". The Journal of Biological Chemistry. 269 (49): 30761–30764. doi:10.1016/S0021-9258(18)47344-9. PMID 7983002.
- Takahashi A, Alnemri ES, Lazebnik YA, Fernandes-Alnemri T, Litwack G, Moir RD, et al. (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". Proceedings of the National Academy of Sciences of the United States of America. 93 (16): 8395–8400. Bibcode:1996PNAS...93.8395T. doi:10.1073/pnas.93.16.8395. PMC 38682. PMID 8710882.
- Bullrich F, Fernandes-Alnemri T, Litwack G, Alnemri ES, Croce CM (1997). "Chromosomal mapping of cell death proteases CPP32, MCH2, and MCH3". Genomics. 36 (2): 362–365. doi:10.1006/geno.1996.0476. PMID 8812467.
- Srinivasula SM, Fernandes-Alnemri T, Zangrilli J, Robertson N, Armstrong RC, Wang L, et al. (1996). "The Ced-3/interleukin 1beta converting enzyme-like homolog Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator CPP32". The Journal of Biological Chemistry. 271 (43): 27099–27106. doi:10.1074/jbc.271.43.27099. PMID 8900201.
- Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Litwack G, Alnemri ES (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". Proceedings of the National Academy of Sciences of the United States of America. 93 (25): 14486–14491. Bibcode:1996PNAS...9314486S. doi:10.1073/pnas.93.25.14486. PMC 26159. PMID 8962078.
- Rao L, Perez D, White E (1997). "Lamin proteolysis facilitates nuclear events during apoptosis". The Journal of Cell Biology. 135 (6 Pt 1): 1441–1455. doi:10.1083/jcb.135.6.1441. PMC 2133948. PMID 8978814.
- Kim TW, Pettingell WH, Jung YK, Kovacs DM, Tanzi RE (1998). "Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease". Science. 277 (5324): 373–376. CiteSeerX 10.1.1.1025.8052. doi:10.1126/science.277.5324.373. PMID 9219695.
- Srinivasula SM, Ahmad M, Ottilie S, Bullrich F, Banks S, Wang Y, et al. (1997). "FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis". The Journal of Biological Chemistry. 272 (30): 18542–18545. doi:10.1074/jbc.272.30.18542. PMID 9228018.
- Caulín C, Salvesen GS, Oshima RG (1997). "Caspase Cleavage of Keratin 18 and Reorganization of Intermediate Filaments during Epithelial Cell Apoptosis". The Journal of Cell Biology. 138 (6): 1379–1394. doi:10.1083/jcb.138.6.1379. PMC 2132555. PMID 9298992.
- Hirata H, Takahashi A, Kobayashi S, Yonehara S, Sawai H, Okazaki T, et al. (1998). "Caspases Are Activated in a Branched Protease Cascade and Control Distinct Downstream Processes in Fas-induced Apoptosis". The Journal of Experimental Medicine. 187 (4): 587–600. doi:10.1084/jem.187.4.587. PMC 2212161. PMID 9463409.
- Harvey KF, Harvey NL, Michael JM, Parasivam G, Waterhouse N, Alnemri ES, et al. (1998). "Caspase-mediated cleavage of the ubiquitin-protein ligase Nedd4 during apoptosis". The Journal of Biological Chemistry. 273 (22): 13524–13530. doi:10.1074/jbc.273.22.13524. PMID 9593687.
- Utz PJ, Hottelet M, Le TM, Kim SJ, Geiger ME, van Venrooij WJ, et al. (1999). "The 72-kDa component of signal recognition particle is cleaved during apoptosis". The Journal of Biological Chemistry. 273 (52): 35362–35370. doi:10.1074/jbc.273.52.35362. PMID 9857079.
- Samejima K, Svingen PA, Basi GS, Kottke T, Mesner PW, Stewart L, et al. (1999). "Caspase-mediated cleavage of DNA topoisomerase I at unconventional sites during apoptosis". The Journal of Biological Chemistry. 274 (7): 4335–4340. doi:10.1074/jbc.274.7.4335. PMID 9933635.
- Walter J, Schindzielorz A, Grünberg J, Haass C (1999). "Phosphorylation of presenilin-2 regulates its cleavage by caspases and retards progression of apoptosis". Proceedings of the National Academy of Sciences of the United States of America. 96 (4): 1391–1396. Bibcode:1999PNAS...96.1391W. doi:10.1073/pnas.96.4.1391. PMC 15473. PMID 9990034.
- van de Craen M, de Jonghe C, van den Brande I, Declercq W, van Gassen G, van Criekinge W, et al. (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 Letters. 445 (1): 149–154. doi:10.1016/S0014-5793(99)00108-8. hdl:10067/238040151162165141. PMID 10069390. S2CID 31218178.
- Xanthoudakis S, Roy S, Rasper D, Hennessey T, Aubin Y, Cassady R, et al. (1999). "Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis". The EMBO Journal. 18 (8): 2049–2056. doi:10.1093/emboj/18.8.2049. PMC 1171289. PMID 10205159.