Caspase 6

Last updated
CASP6
Protein CASP6 PDB 1MI9.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CASP6 , MCH2, Caspase 6, CSP-6
External IDs OMIM: 601532; MGI: 1312921; HomoloGene: 37455; GeneCards: CASP6; OMA:CASP6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001226
NM_032992

NM_009811

RefSeq (protein)

NP_001217
NP_116787

NP_033941

Location (UCSC) Chr 4: 109.69 – 109.7 Mb Chr 3: 129.7 – 129.71 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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

Related Research Articles

<span class="mw-page-title-main">Caspase</span> Family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

<span class="mw-page-title-main">BH3 interacting-domain death agonist</span> Protein-coding gene in the species Homo sapiens

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

<span class="mw-page-title-main">Caspase-9</span> Enzyme found in humans

Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such as Mus musculus and Pan troglodytes.

<span class="mw-page-title-main">Caspase 8</span> Protein found in humans

Caspase-8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase-3. CASP8 orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present in birds.

<span class="mw-page-title-main">Caspase 2</span> Enzyme found in humans

Caspase 2 also known as CASP2 is an enzyme that, in humans, is encoded by the CASP2 gene. CASP2 orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

<span class="mw-page-title-main">Caspase 3</span> Protein found in humans

Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the CASP3 gene. CASP3 orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

<span class="mw-page-title-main">Caspase 7</span> Protein found in humans

Caspase-7, apoptosis-related cysteine peptidase, also known as CASP7, is a human protein encoded by the CASP7 gene. CASP7 orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

<span class="mw-page-title-main">Baculoviral IAP repeat-containing protein 2</span> Protein-coding gene in the species Homo sapiens

Baculoviral IAP repeat-containing protein 2 is a protein that in humans is encoded by the BIRC2 gene.

<span class="mw-page-title-main">Caspase 10</span> Enzyme found in humans

Caspase-10 is an enzyme that, in humans, is encoded by the CASP10 gene.

<span class="mw-page-title-main">Calpain-2 catalytic subunit</span> Protein-coding gene in the species Homo sapiens

Calpain-2 catalytic subunit is a protein that in humans is encoded by the CAPN2 gene.

<span class="mw-page-title-main">Diablo homolog</span> Protein-coding gene in the species Homo sapiens

Diablo homolog (DIABLO) is a mitochondrial protein that in humans is encoded by the DIABLO gene on chromosome 12. DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC. This protein binds inhibitor of apoptosis proteins (IAPs), thus freeing caspases to activate apoptosis. Due to its proapoptotic function, SMAC is implicated in a broad spectrum of tumors, and small molecule SMAC mimetics have been developed to enhance current cancer treatments.

<span class="mw-page-title-main">APAF1</span> Mammalian protein found in Homo sapiens

Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of C. elegans CED-4 gene.

<span class="mw-page-title-main">PYCARD</span> Human protein and coding gene

PYCARD, often referred to as ASC, is a protein that in humans is encoded by the PYCARD gene. It is localized mainly in the nucleus of monocytes and macrophages. In case of pathogen infection, however, it relocalizes rapidly to the cytoplasm, perinuclear space, endoplasmic reticulum and mitochondria and it is a key adaptor protein in activation of the inflammasome.

<span class="mw-page-title-main">Serine protease HTRA2, mitochondrial</span> Enzyme found in humans

Serine protease HTRA2, mitochondrial is an enzyme that in humans is encoded by the HTRA2 gene. This protein is involved in caspase-dependent apoptosis and in Parkinson's disease.

<span class="mw-page-title-main">CRADD</span> Protein-coding gene in humans

Death domain-containing protein CRADD is a protein that in humans is encoded by the CRADD gene.

<span class="mw-page-title-main">DEDD</span> Protein-coding gene in humans

Death effector domain containing protein is a protein that in humans is encoded by the DEDD gene.

<span class="mw-page-title-main">COP1</span> Protein-coding gene in the species Homo sapiens

Fagol Caspase recruitment domain-containing protein 16 is an enzyme that in humans is encoded by the CARD16 gene.

<span class="mw-page-title-main">Early 35 kDa protein</span> Anti-apoptotic viral protein

The Early 35 kDa protein, or P35 in short, is a baculoviral protein that inhibits apoptosis in the cells infected by the virus. Although baculoviruses infect only invertebrates in nature, ectopic expression of P35 in vertebrate animals and cells also results in inhibition of apoptosis, thus indicating a universal mechanism. P35 has been shown to be a caspase inhibitor with a very wide spectrum of activity both in regard to inhibited caspase types and to species in which the mechanism is conserved.

<span class="mw-page-title-main">Sf caspase-1</span>

The protein Sf caspase-1 is the insect ortholog of the human effector caspases CASP3 (CPP32) and CASP7 (MCH3) in the species Spodoptera frugiperda. It was identified as the target of the baculoviral caspase inhibitor protein P35, which it cleaves and by which it is inhibited. Like other caspases, Sf caspase-1 is an aspartate-specific cysteine protease that is produced as an inactive proenzyme and becomes activated by autocatalytic cleavage. The Sf caspase-1 proenzyme is cleaved after the amino acid residues Asp-28 and Asp-195, resulting in a smaller 12 kDa fragment and a larger 19 kDa fragment. Just like with human caspases CASP3 or CASP7, the two cleavage fragments form heterodimers, which again form biologically active dimers-of-heterodimers consisting of two smaller and two larger fragments. Some experiments also showed cleavage of Sf caspase-1 at the residue Asp-184, resulting in an 18 kDa instead of 19 kDa fragment, however this result is likely an in vitro artefact. The insect immunophilin FKBP46 is a substrate of Sf caspase-1, which cleaves full length FKBP46 resulting in a ~25 kDa fragment.

<span class="mw-page-title-main">S. Murty Srinivasula</span> Indian cell biologist

Srinivasa Murty Srinivasula is an Indian cell biologist, a professor at the School of Biology at the Indian Institute of Science Education and Research, Thiruvananthapuram in Kerala, India. His research field is apoptosis, autophagy and oncology.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000138794 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000027997 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Tiso N, Pallavicini A, Muraro T, Zimbello R, Apolloni E, Valle G, Lanfranchi G, Danieli GA (Oct 1996). "Chromosomal localization of the human genes, CPP32, Mch2, Mch3, and Ich-1, involved in cellular apoptosis". Biochem Biophys Res Commun. 225 (3): 983–9. doi:10.1006/bbrc.1996.1282. PMID   8780721.
  6. Fernandes-Alnemri T, Litwack G, Alnemri ES (Aug 1995). "Mch2, a new member of the apoptotic Ced-3/Ice cysteine protease gene family". Cancer Res. 55 (13): 2737–42. PMID   7796396.
  7. "OrthoMaM phylogenetic marker: CASP6 coding sequence". Archived from the original on 2016-03-03. Retrieved 2009-12-20.
  8. 1 2 Cohen, Gerald M. (1997-08-15). "Caspases: the executioners of apoptosis". Biochemical Journal. 326 (1): 1–16. doi:10.1042/bj3260001. ISSN   0264-6021. PMC   1218630 . PMID   9337844.
  9. 1 2 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. Bibcode:2017PLoSO..1280203B. doi: 10.1371/journal.pone.0180203 . ISSN   1932-6203. PMC   5501493 . PMID   28686630.
  10. 1 2 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. 186 (1): 403–410. doi:10.4049/jimmunol.1001906. ISSN   0022-1767. PMC   3151149 . PMID   21098228.
  11. 1 2 Graham, Rona K.; Ehrnhoefer, Dagmar E.; Hayden, Michael R. (2011-12-01). "Caspase-6 and neurodegeneration". Trends in Neurosciences. 34 (12): 646–656. doi:10.1016/j.tins.2011.09.001. ISSN   0166-2236. PMID   22018804. S2CID   1603684.
  12. Wang XJ, Cao Q, Liu X, Wang KT, Mi W, Zhang Y, Li LF, LeBlanc AC, Su XD (Nov 2010). "Crystal structures of human caspase 6 reveal a new mechanism for intramolecular cleavage self-activation". EMBO Rep. 11 (11): 841–7. doi:10.1038/embor.2010.141. PMC   2966951 . PMID   20890311.
  13. "Entrez Gene: CASP6 caspase 6, apoptosis-related cysteine peptidase".
  14. 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 Differ. 9 (10): 1046–56. doi: 10.1038/sj.cdd.4401065 . PMID   12232792.
  15. Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES (Apr 2002). "Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria". J. Biol. Chem. 277 (16): 13430–7. doi: 10.1074/jbc.M108029200 . PMID   11832478.
  16. 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". Proc. Natl. Acad. Sci. U.S.A. 93 (25): 14486–91. Bibcode:1996PNAS...9314486S. doi: 10.1073/pnas.93.25.14486 . PMC   26159 . PMID   8962078.

Further reading