Caspase 8

Last updated
CASP8
Protein CASP8 PDB 1f9e.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CASP8 , ALPS2B, CAP4, Casp-8, FLICE, MACH, MCH5, caspase 8
External IDs OMIM: 601763; MGI: 1261423; HomoloGene: 7657; GeneCards: CASP8; OMA:CASP8 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001080126
NM_001277926
NM_009812

RefSeq (protein)

NP_001073595
NP_001264855
NP_033942

Location (UCSC) Chr 2: 201.23 – 201.29 Mb Chr 1: 58.83 – 58.89 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Caspase-8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase-3. CASP8 orthologs [5] have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present in birds.

Function

The CASP8 gene encodes 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 composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. [6]

Clinical significance

A very rare genetic disorder of the immune system can also be caused by mutations in this gene. This disease, called CEDS, stands for “Caspase eight deficiency state.” CEDS has features similar to ALPS, another genetic disease of apoptosis, with the addition of an immunodeficient phenotype. Thus, the clinical manifestations include splenomegaly and lymphadenopathy, in addition to recurrent sinopulmonary infections, recurrent mucocutaneous herpesvirus, persistent warts and molluscum contagiosum infections, and hypogammaglobulinemia. There is sometimes lymphocytic infiltrative disease in parenchymal organs, but autoimmunity is minimal and lymphoma has not been observed in the CEDS patients. CEDS is inherited in an autosomal recessive manner. [7]

The clinical phenotype of CEDS patients represented a paradox since caspase-8 was considered to be chiefly a proapoptotic protease, that was mainly involved in signal transduction from Tumor necrosis factor receptor family death receptors such as Fas. The defect in lymphocyte activation and protective immunity suggested that caspase-8 had additional signaling roles in lymphocytes. Further work revealed that caspase-8 was essential for the induction of the transcription factor “nuclear factor κB” (NF-κB) after stimulation through antigen receptors, Fc receptors, or Toll-like receptor 4 in T, B, and natural killer cells. [7]

Biochemically, caspase-8 was found to enter the complex of the inhibitor of NF-κB kinase (IKK) with the upstream Bcl10-MALT1 (mucosa-associated lymphatic tissue) adapter complex which were crucial for the induction of nuclear translocation of NF-κB. Moreover, the biochemical form of caspase-8 differed in the two pathways. For the death pathway, the caspase-8 zymogen is cleaved into subunits that assemble to form the mature, highly active caspase heterotetramer whereas for the activation pathway, the zymogen appears to remain intact perhaps to limit its proteolytic function but enhance its capability as an adapter protein. [7]

Interactions

Caspase-8 has been shown to interact with:

Additional photos

Signaling pathway of TNF-R1. Dashed grey lines represent multiple steps TNF signaling.jpg
Signaling pathway of TNF-R1. Dashed grey lines represent multiple steps
Overview of signal transduction pathways involved in apoptosis. Signal transduction pathways.svg
Overview of signal transduction pathways involved in apoptosis.

See also

Related Research Articles

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

Fas ligand is a type-II transmembrane protein expressed on various types of cells, including cytotoxic T lymphocytes, monocytes, neutrophils, breast epithelial cells, vascular endothelial cells and natural killer (NK) cells. It binds with its receptor, called FAS receptor and plays a crucial role in the regulation of the immune system and in induction of apoptosis, a programmed cell death.

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

The Fas receptor, also known as Fas, FasR, apoptosis antigen 1, cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a protein that in humans is encoded by the FAS gene. Fas was first identified using a monoclonal antibody generated by immunizing mice with the FS-7 cell line. Thus, the name Fas is derived from FS-7-associated surface antigen.

<span class="mw-page-title-main">Death-inducing signaling complex</span>

The death-inducing signaling complex or DISC is a multi-protein complex formed by members of the death receptor family of apoptosis-inducing cellular receptors. A typical example is FasR, which forms the DISC upon trimerization as a result of its ligand (FasL) binding. The DISC is composed of the death receptor, FADD, and caspase 8. It transduces a downstream signal cascade resulting in apoptosis.

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

FAS-associated death domain protein, also called MORT1, is encoded by the FADD gene on the 11q13.3 region of chromosome 11 in humans.

<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 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">Caspase 6</span> Enzyme found in humans

Caspase-6 is an enzyme that in humans is encoded by the CASP6 gene. CASP6 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. Caspase-6 has known functions in apoptosis, early immune response and neurodegeneration in Huntington's and Alzheimer's disease.

<span class="mw-page-title-main">Death receptor 4</span> Protein found in humans

Death receptor 4 (DR4), also known as TRAIL receptor 1 (TRAILR1) and tumor necrosis factor receptor superfamily member 10A (TNFRSF10A), is a cell surface receptor of the TNF-receptor superfamily that binds TRAIL and mediates apoptosis.

<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">Death receptor 5</span> Protein found in humans

Death receptor 5 (DR5), also known as TRAIL receptor 2 (TRAILR2) and tumor necrosis factor receptor superfamily member 10B (TNFRSF10B), is a cell surface receptor of the TNF-receptor superfamily that binds TRAIL and mediates apoptosis.

<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">BCL10</span> Protein-coding gene in the species Homo sapiens

B-cell lymphoma/leukemia 10 is a protein that in humans is encoded by the BCL10 gene. Like BCL2, BCL3, BCL5, BCL6, BCL7A, and BCL9, it has clinical significance in lymphoma.

<span class="mw-page-title-main">RIPK2</span> Protein-coding gene in humans

Receptor-interacting serine/threonine-protein kinase 2 is an enzyme that in humans is encoded by the RIPK2 gene.

<span class="mw-page-title-main">CASP8AP2</span> Protein-coding gene in the species Homo sapiens

CASP8-associated protein 2 is a protein, that in humans is encoded by the CASP8AP2 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.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000064012 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026029 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. "OrthoMaM phylogenetic marker: CASP8 coding sequence".[ permanent dead link ]
  6. "Entrez Gene: CASP8 caspase 8, apoptosis-related cysteine peptidase".
  7. 1 2 3 Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM, Dale JK, Puck J, Davis J, Hall CG, Skoda-Smith S, Atkinson TP, Straus SE, Lenardo MJ (2002). "Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency". Nature. 419 (6905): 395–9. Bibcode:2002Natur.419..395C. doi:10.1038/nature01063. PMID   12353035. S2CID   4359174.
  8. Ng FW, Nguyen M, Kwan T, Branton PE, Nicholson DW, Cromlish JA, Shore GC (October 1997). "p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the endoplasmic reticulum". J. Cell Biol. 139 (2): 327–38. doi:10.1083/jcb.139.2.327. PMC   2139787 . PMID   9334338.
  9. 1 2 3 4 5 6 Gajate C, Mollinedo F (March 2005). "Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy". J. Biol. Chem. 280 (12): 11641–7. doi: 10.1074/jbc.M411781200 . PMID   15659383.
  10. 1 2 3 4 5 6 7 8 Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES (April 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.
  11. Poulaki V, Mitsiades N, Romero ME, Tsokos M (June 2001). "Fas-mediated apoptosis in neuroblastoma requires mitochondrial activation and is inhibited by FLICE inhibitor protein and Bcl-2". Cancer Res. 61 (12): 4864–72. PMID   11406564.
  12. 1 2 3 4 5 Micheau O, Tschopp J (July 2003). "Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes" (PDF). Cell. 114 (2): 181–90. doi:10.1016/s0092-8674(03)00521-x. PMID   12887920. S2CID   17145731.
  13. 1 2 Shu HB, Halpin DR, Goeddel DV (June 1997). "Casper is a FADD- and caspase-related inducer of apoptosis". Immunity. 6 (6): 751–63. doi: 10.1016/s1074-7613(00)80450-1 . PMID   9208847.
  14. Goltsev YV, Kovalenko AV, Arnold E, Varfolomeev EE, Brodianskii VM, Wallach D (August 1997). "CASH, a novel caspase homologue with death effector domains". J. Biol. Chem. 272 (32): 19641–4. doi: 10.1074/jbc.272.32.19641 . PMID   9289491.
  15. 1 2 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 (July 1997). "FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis". J. Biol. Chem. 272 (30): 18542–5. doi: 10.1074/jbc.272.30.18542 . PMID   9228018.
  16. Micheau O, Thome M, Schneider P, Holler N, Tschopp J, Nicholson DW, Briand C, Grütter MG (November 2002). "The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex". J. Biol. Chem. 277 (47): 45162–71. doi: 10.1074/jbc.M206882200 . PMID   12215447.
  17. Han DK, Chaudhary PM, Wright ME, Friedman C, Trask BJ, Riedel RT, Baskin DG, Schwartz SM, Hood L (October 1997). "MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death". Proc. Natl. Acad. Sci. U.S.A. 94 (21): 11333–8. Bibcode:1997PNAS...9411333H. doi: 10.1073/pnas.94.21.11333 . PMC   23459 . PMID   9326610.
  18. Roth W, Stenner-Liewen F, Pawlowski K, Godzik A, Reed JC (March 2002). "Identification and characterization of DEDD2, a death effector domain-containing protein". J. Biol. Chem. 277 (9): 7501–8. doi: 10.1074/jbc.M110749200 . PMID   11741985.
  19. 1 2 3 4 5 6 Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Litwack G, Alnemri ES (December 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.
  20. Cowling V, Downward J (October 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.
  21. Zhan Y, Hegde R, Srinivasula SM, Fernandes-Alnemri T, Alnemri ES (April 2002). "Death effector domain-containing proteins DEDD and FLAME-3 form nuclear complexes with the TFIIIC102 subunit of human transcription factor IIIC". Cell Death Differ. 9 (4): 439–47. doi: 10.1038/sj.cdd.4401038 . PMID   11965497.
  22. Alcivar A, Hu S, Tang J, Yang X (January 2003). "DEDD and DEDD2 associate with caspase-8/10 and signal cell death". Oncogene. 22 (2): 291–7. doi: 10.1038/sj.onc.1206099 . PMID   12527898.
  23. Stegh AH, Schickling O, Ehret A, Scaffidi C, Peterhänsel C, Hofmann TG, Grummt I, Krammer PH, Peter ME (October 1998). "DEDD, a novel death effector domain-containing protein, targeted to the nucleolus". EMBO J. 17 (20): 5974–86. doi:10.1093/emboj/17.20.5974. PMC   1170924 . PMID   9774341.
  24. 1 2 Oshima S, Turer EE, Callahan JA, Chai S, Advincula R, Barrera J, Shifrin N, Lee B, Benedict Yen TS, Yen B, Woo T, Malynn BA, Ma A (February 2009). "ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development". Nature. 457 (7231): 906–9. Bibcode:2009Natur.457..906O. doi:10.1038/nature07575. PMC   2642523 . PMID   19060883.
  25. Henshall DC, Araki T, Schindler CK, Shinoda S, Lan JQ, Simon RP (September 2003). "Expression of death-associated protein kinase and recruitment to the tumor necrosis factor signaling pathway following brief seizures". J. Neurochem. 86 (5): 1260–70. doi: 10.1046/j.1471-4159.2003.01934.x . PMID   12911633. S2CID   21971958.
  26. Boldin MP, Goncharov TM, Goltsev YV, Wallach D (June 1996). "Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death". Cell. 85 (6): 803–15. doi: 10.1016/s0092-8674(00)81265-9 . PMID   8681376. S2CID   7415784.
  27. Thomas LR, Stillman DJ, Thorburn A (September 2002). "Regulation of Fas-associated death domain interactions by the death effector domain identified by a modified reverse two-hybrid screen". J. Biol. Chem. 277 (37): 34343–8. doi: 10.1074/jbc.M204169200 . PMID   12107169.
  28. 1 2 MacFarlane M, Ahmad M, Srinivasula SM, Fernandes-Alnemri T, Cohen GM, Alnemri ES (October 1997). "Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL". J. Biol. Chem. 272 (41): 25417–20. doi: 10.1074/jbc.272.41.25417 . PMID   9325248.
  29. Gervais FG, Singaraja R, Xanthoudakis S, Gutekunst CA, Leavitt BR, Metzler M, Hackam AS, Tam J, Vaillancourt JP, Houtzager V, Rasper DM, Roy S, Hayden MR, Nicholson DW (February 2002). "Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi". Nat. Cell Biol. 4 (2): 95–105. doi:10.1038/ncb735. PMID   11788820. S2CID   10439592.
  30. Koseki T, Inohara N, Chen S, Núñez G (April 1998). "ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases". Proc. Natl. Acad. Sci. U.S.A. 95 (9): 5156–60. Bibcode:1998PNAS...95.5156K. doi: 10.1073/pnas.95.9.5156 . PMC   20230 . PMID   9560245.
  31. Kitsberg D, Formstecher E, Fauquet M, Kubes M, Cordier J, Canton B, Pan G, Rolli M, Glowinski J, Chneiweiss H (October 1999). "Knock-out of the neural death effector domain protein PEA-15 demonstrates that its expression protects astrocytes from TNFalpha-induced apoptosis". J. Neurosci. 19 (19): 8244–51. doi:10.1523/JNEUROSCI.19-19-08244.1999. PMC   6783010 . PMID   10493725.
  32. Condorelli G, Vigliotta G, Cafieri A, Trencia A, Andalò P, Oriente F, Miele C, Caruso M, Formisano P, Beguinot F (August 1999). "PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis". Oncogene. 18 (31): 4409–15. doi:10.1038/sj.onc.1202831. PMID   10442631. S2CID   20510429.
  33. Chaudhary PM, Eby MT, Jasmin A, Kumar A, Liu L, Hood L (September 2000). "Activation of the NF-kappaB pathway by caspase 8 and its homologs". Oncogene. 19 (39): 4451–60. doi: 10.1038/sj.onc.1203812 . PMID   11002417.
  34. Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J, Gillard JW, Jaquith JB, Morris SJ, Barker PA (June 2008). "cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination". Mol. Cell. 30 (6): 689–700. doi: 10.1016/j.molcel.2008.05.014 . PMID   18570872.
  35. Leo E, Deveraux QL, Buchholtz C, Welsh K, Matsuzawa S, Stennicke HR, Salvesen GS, Reed JC (March 2001). "TRAF1 is a substrate of caspases activated during tumor necrosis factor receptor-alpha-induced apoptosis". J. Biol. Chem. 276 (11): 8087–93. doi: 10.1074/jbc.M009450200 . PMID   11098060.

Further reading