Caspase-8 is a
caspase protein, encoded by the CASP8 gene. It most likely acts upon
caspase-3.
CASP8orthologs[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 acidprotease (
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
mucocutaneousherpesvirus, 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
proapoptoticprotease, 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-κBkinase (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]
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^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.
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