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
editThe 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
editA 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
editCaspase-8 has been shown to interact with:
- BCAP31,[8]
- BID,[9][10]
- Bcl-2,[10][11]
- CFLAR,[12][13][14][15][16][17][18]
- Caspase-10,[9][10][12][19]
- Caspase-2,[10][19]
- Caspase-3,[10][19]
- Caspase-6,[10][19][20]
- Caspase-7,[10][19]
- Caspase-9,[10][19]
- DEDD,[21][22][23]
- FADD,[9][12][15][24][25][26][27]
- FasL,[9][12]
- FasR,[9][13][28]
- IFT57,[29]
- NOL3,[30]
- PEA15,[31][32]
- RIPK1,[24][33][34]
- TNFRSF10B,[9][28] and
- TRAF1.[12][35]
Additional photos
editSee also
editReferences
edit- ^ a b c GRCh38: Ensembl release 89: ENSG00000064012 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026029 – Ensembl, May 2017
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- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ 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.
- ^ 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.
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- ^ 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.
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- ^ a b 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.
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- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
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Further reading
edit- Jia SH, Parodo J, Kapus A, Rotstein OD, Marshall JC (2008). "Dynamic Regulation of Neutrophil Survival through Tyrosine Phosphorylation or Dephosphorylation of Caspase-8". Journal of Biological Chemistry. 283 (9): 5402–5413. doi:10.1074/jbc.M706462200. PMID 18086677.
- Cohen GM (1997). "Caspases: the executioners of apoptosis". Biochem. J. 326 (Pt 1): 1–16. doi:10.1042/bj3260001. PMC 1218630. PMID 9337844.
- Siegel RM, Chan FK, Chun HJ, Lenardo MJ (2001). "The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity". Nat. Immunol. 1 (6): 469–74. doi:10.1038/82712. PMID 11101867. S2CID 345769.
- Ye S, Goldsmith EJ (2002). "Serpins and other covalent protease inhibitors". Curr. Opin. Struct. Biol. 11 (6): 740–5. doi:10.1016/S0959-440X(01)00275-5. PMID 11751056.
- Gupta S (2002). "Tumor necrosis factor-alpha-induced apoptosis in T cells from aged humans: a role of TNFR-I and downstream signaling molecules". Exp. Gerontol. 37 (2–3): 293–9. doi:10.1016/S0531-5565(01)00195-4. PMID 11772515. S2CID 30243363.
- Pomerantz RJ (2004). "Effects of HIV-1 Vpr on neuroinvasion and neuropathogenesis". DNA Cell Biol. 23 (4): 227–38. doi:10.1089/104454904773819815. PMID 15142380.
- Zhao LJ, Zhu H (2005). "Structure and function of HIV-1 auxiliary regulatory protein Vpr: novel clues to drug design". Curr. Drug Targets Immune Endocr. Metabol. Disord. 4 (4): 265–75. doi:10.2174/1568008043339668. PMID 15578977.
External links
edit- The MEROPS online database for peptidases and their inhibitors: C14.009[permanent dead link]
- Apoptosis & Caspase 8—The Proteolysis Map (animation)
- Caspase+8 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- caspase-8
- Overview of all the structural information available in the PDB for UniProt: Q14790 (Caspase-8) at the PDBe-KB.