Biology:Caspase 8
![]() Generic protein structure example |
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.
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.[2]
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.[3]
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.[3]
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.[3]
Interactions
Caspase-8 has been shown to interact with:
- BCAP31,[4]
- BID,[5][6]
- Bcl-2,[6][7]
- CFLAR,[8][9][10][11][12][13][14]
- Caspase-10,[5][6][8][15]
- Caspase-2,[6][15]
- Caspase-3,[6][15]
- Caspase-6,[6][15][16]
- Caspase-7,[6][15]
- Caspase-9,[6][15]
- DEDD,[17][18][19]
- FADD,[5][8][11][20][21][22][23]
- FasL,[5][8]
- FasR,[5][9][24]
- IFT57,[25]
- NOL3,[26]
- PEA15,[27][28]
- RIPK1,[20][29][30]
- TNFRSF10B,[5][24] and
- TRAF1.[8][31]
Additional photos
200px|thumb|Overview of signal transduction pathways involved in apoptosis. |
See also
References
- ↑ "OrthoMaM phylogenetic marker: CASP8 coding sequence". http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000064012_CASP8.xml.[yes|permanent dead link|dead link}}]
- ↑ "Entrez Gene: CASP8 caspase 8, apoptosis-related cysteine peptidase". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=841.
- ↑ 3.0 3.1 3.2 "Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency". Nature 419 (6905): 395–9. 2002. doi:10.1038/nature01063. PMID 12353035. Bibcode: 2002Natur.419..395C. https://zenodo.org/record/1233255.
- ↑ "p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the endoplasmic reticulum". J. Cell Biol. 139 (2): 327–38. October 1997. doi:10.1083/jcb.139.2.327. PMID 9334338.
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy". J. Biol. Chem. 280 (12): 11641–7. March 2005. doi:10.1074/jbc.M411781200. PMID 15659383.
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 "Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria". J. Biol. Chem. 277 (16): 13430–7. April 2002. doi:10.1074/jbc.M108029200. PMID 11832478.
- ↑ "Fas-mediated apoptosis in neuroblastoma requires mitochondrial activation and is inhibited by FLICE inhibitor protein and Bcl-2". Cancer Res. 61 (12): 4864–72. June 2001. PMID 11406564.
- ↑ 8.0 8.1 8.2 8.3 8.4 "Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes". Cell 114 (2): 181–90. July 2003. doi:10.1016/s0092-8674(03)00521-x. PMID 12887920. https://www.hal.inserm.fr/inserm-00527105/file/Figures_Cell_OM.pdf.
- ↑ 9.0 9.1 "Casper is a FADD- and caspase-related inducer of apoptosis". Immunity 6 (6): 751–63. June 1997. doi:10.1016/s1074-7613(00)80450-1. PMID 9208847.
- ↑ "CASH, a novel caspase homologue with death effector domains". J. Biol. Chem. 272 (32): 19641–4. August 1997. doi:10.1074/jbc.272.32.19641. PMID 9289491.
- ↑ 11.0 11.1 "FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis". J. Biol. Chem. 272 (30): 18542–5. July 1997. doi:10.1074/jbc.272.30.18542. PMID 9228018.
- ↑ "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. November 2002. doi:10.1074/jbc.M206882200. PMID 12215447.
- ↑ "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. October 1997. doi:10.1073/pnas.94.21.11333. PMID 9326610. Bibcode: 1997PNAS...9411333H.
- ↑ "Identification and characterization of DEDD2, a death effector domain-containing protein". J. Biol. Chem. 277 (9): 7501–8. March 2002. doi:10.1074/jbc.M110749200. PMID 11741985.
- ↑ 15.0 15.1 15.2 15.3 15.4 15.5 "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. December 1996. doi:10.1073/pnas.93.25.14486. PMID 8962078. Bibcode: 1996PNAS...9314486S.
- ↑ "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. October 2002. doi:10.1038/sj.cdd.4401065. PMID 12232792.
- ↑ "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. April 2002. doi:10.1038/sj.cdd.4401038. PMID 11965497.
- ↑ "DEDD and DEDD2 associate with caspase-8/10 and signal cell death". Oncogene 22 (2): 291–7. January 2003. doi:10.1038/sj.onc.1206099. PMID 12527898.
- ↑ "DEDD, a novel death effector domain-containing protein, targeted to the nucleolus". EMBO J. 17 (20): 5974–86. October 1998. doi:10.1093/emboj/17.20.5974. PMID 9774341.
- ↑ 20.0 20.1 "ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development". Nature 457 (7231): 906–9. February 2009. doi:10.1038/nature07575. PMID 19060883. Bibcode: 2009Natur.457..906O.
- ↑ "Expression of death-associated protein kinase and recruitment to the tumor necrosis factor signaling pathway following brief seizures". J. Neurochem. 86 (5): 1260–70. September 2003. doi:10.1046/j.1471-4159.2003.01934.x. PMID 12911633.
- ↑ "Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death". Cell 85 (6): 803–15. June 1996. doi:10.1016/s0092-8674(00)81265-9. PMID 8681376.
- ↑ "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. September 2002. doi:10.1074/jbc.M204169200. PMID 12107169.
- ↑ 24.0 24.1 "Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL". J. Biol. Chem. 272 (41): 25417–20. October 1997. doi:10.1074/jbc.272.41.25417. PMID 9325248.
- ↑ "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. February 2002. doi:10.1038/ncb735. PMID 11788820.
- ↑ "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. April 1998. doi:10.1073/pnas.95.9.5156. PMID 9560245. Bibcode: 1998PNAS...95.5156K.
- ↑ "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. October 1999. doi:10.1523/JNEUROSCI.19-19-08244.1999. PMID 10493725.
- ↑ "PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis". Oncogene 18 (31): 4409–15. August 1999. doi:10.1038/sj.onc.1202831. PMID 10442631.
- ↑ "Activation of the NF-kappaB pathway by caspase 8 and its homologs". Oncogene 19 (39): 4451–60. September 2000. doi:10.1038/sj.onc.1203812. PMID 11002417.
- ↑ "cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination". Mol. Cell 30 (6): 689–700. June 2008. doi:10.1016/j.molcel.2008.05.014. PMID 18570872.
- ↑ "TRAF1 is a substrate of caspases activated during tumor necrosis factor receptor-alpha-induced apoptosis". J. Biol. Chem. 276 (11): 8087–93. March 2001. doi:10.1074/jbc.M009450200. PMID 11098060.
Further reading
- "Dynamic Regulation of Neutrophil Survival through Tyrosine Phosphorylation or Dephosphorylation of Caspase-8". Journal of Biological Chemistry 283 (9): 5402–5413. 2008. doi:10.1074/jbc.M706462200. PMID 18086677.
- "Caspases: the executioners of apoptosis". Biochem. J. 326 (Pt 1): 1–16. 1997. doi:10.1042/bj3260001. PMID 9337844.
- "The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity". Nat. Immunol. 1 (6): 469–74. 2001. doi:10.1038/82712. PMID 11101867.
- "Serpins and other covalent protease inhibitors". Curr. Opin. Struct. Biol. 11 (6): 740–5. 2002. doi:10.1016/S0959-440X(01)00275-5. PMID 11751056.
- "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. 2002. doi:10.1016/S0531-5565(01)00195-4. PMID 11772515.
- "Effects of HIV-1 Vpr on neuroinvasion and neuropathogenesis". DNA Cell Biol. 23 (4): 227–38. 2004. doi:10.1089/104454904773819815. PMID 15142380.
- "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. 2005. doi:10.2174/1568008043339668. PMID 15578977.
External links
- The MEROPS online database for peptidases and their inhibitors: C14.009
- Apoptosis & Caspase 8—The Proteolysis Map (animation)
- Caspase+8 at the US 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.
![]() | Original source: https://en.wikipedia.org/wiki/Caspase 8.
Read more |