Caspase 8

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Caspase 8, apoptosis-related cysteine peptidase
Protein CASP8 PDB 1f9e.png
PDB rendering based on 1f9e.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols CASP8 ; ALPS2B; CAP4; Casp-8; FLICE; MACH; MCH5
External IDs OMIM601763 MGI1261423 HomoloGene7657 ChEMBL: 3776 GeneCards: CASP8 Gene
EC number
RNA expression pattern
PBB GE CASP8 213373 s at tn.png
PBB GE CASP8 207686 s at tn.png
More reference expression data
Species Human Mouse
Entrez 841 12370
Ensembl ENSG00000064012 ENSMUSG00000026029
UniProt Q14790 O89110
RefSeq (mRNA) NM_001080124 NM_001080126
RefSeq (protein) NP_001073593 NP_001073595
Location (UCSC) Chr 2:
202.1 – 202.15 Mb
Chr 1:
58.8 – 58.85 Mb
PubMed search [1] [2]

Caspase-8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase-3. CASP8 orthologs [1] have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present in birds.


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.[2]

Clinical significance[edit]

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.” It is characterized by splenomegaly and lymphadenopathy, in addition to recurrent sinopulmonary infections, recurrent mucocutaneous herpesvirus or other viral infections, and hypogammaglobulinemia.[3]


Caspase-8 has been shown to interact with:

Additional Photos[edit]

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

See also[edit]


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  2. ^ "Entrez Gene: CASP8 caspase 8, apoptosis-related cysteine peptidase". 
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  4. ^ Ng FW, Nguyen M, Kwan T, Branton PE, Nicholson DW, Cromlish JA et al. (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. 
  5. ^ a b c d e f 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. 
  6. ^ a b c d e f g h 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. 
  7. ^ 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. 
  8. ^ a b c d e Micheau O, Tschopp J (July 2003). "Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes". Cell 114 (2): 181–90. doi:10.1016/s0092-8674(03)00521-x. PMID 12887920. 
  9. ^ a b 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. 
  10. ^ 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. 
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  14. ^ 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. 
  15. ^ a b c d e f 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. doi:10.1073/pnas.93.25.14486. PMC 26159. PMID 8962078. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ 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. 
  19. ^ Stegh AH, Schickling O, Ehret A, Scaffidi C, Peterhänsel C, Hofmann TG et al. (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.  Vancouver style error (help)
  20. ^ a b Oshima S, Turer EE, Callahan JA, Chai S, Advincula R, Barrera J et al. (February 2009). "ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development". Nature 457 (7231): 906–9. doi:10.1038/nature07575. PMC 2642523. PMID 19060883. 
  21. ^ 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. 
  22. ^ 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. 
  23. ^ 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. 
  24. ^ a b 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. 
  25. ^ Gervais FG, Singaraja R, Xanthoudakis S, Gutekunst CA, Leavitt BR, Metzler M et al. (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. 
  26. ^ 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. doi:10.1073/pnas.95.9.5156. PMC 20230. PMID 9560245.  Vancouver style error (help)
  27. ^ Kitsberg D, Formstecher E, Fauquet M, Kubes M, Cordier J, Canton B et al. (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. PMID 10493725. 
  28. ^ Condorelli G, Vigliotta G, Cafieri A, Trencia A, Andalò P, Oriente F et al. (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.  Vancouver style error (help)
  29. ^ 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. 
  30. ^ Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J et al. (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. 
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Further reading[edit]

External links[edit]