Caspase 8

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

Function
The CASP8 gene encodes a member of the is_associated_with::cysteine-is_associated_with::aspartic acid is_associated_with::protease (is_associated_with::caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell is_associated_with::apoptosis. Caspases exist as inactive is_associated_with::proenzymes composed of a is_associated_with::prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires is_associated_with::proteolytic processing at conserved internal aspartic residues to generate a is_associated_with::heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the is_associated_with::programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal is_associated_with::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 is_associated_with::Huntington disease patients but not in those from normal controls, which implicated the role in is_associated_with::neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined.

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 is_associated_with::apoptosis, with the addition of an is_associated_with::immunodeficient phenotype. Thus, the clinical manifestations include is_associated_with::splenomegaly and is_associated_with::lymphadenopathy, in addition to recurrent sinopulmonary infections, recurrent is_associated_with::mucocutaneous is_associated_with::herpesvirus, persistent warts and is_associated_with::molluscum contagiosum infections, and is_associated_with::hypogammaglobulinemia. There is sometimes lymphocytic infiltrative disease in is_associated_with::parenchymal organs, but is_associated_with::autoimmunity is minimal and is_associated_with::lymphoma has not been observed in the CEDS patients. CEDS is inherited in an autosomal recessive manner.

The clinical phenotype of CEDS patients represented a is_associated_with::paradox since caspase-8 was considered to be chiefly a is_associated_with::proapoptotic is_associated_with::protease, that was mainly involved in signal transduction from is_associated_with::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 is_associated_with::lymphocytes. Further work revealed that caspase-8 was essential for the induction of the transcription factor “nuclear factor κB” (is_associated_with::NF-κB) after stimulation through is_associated_with::antigen receptors, Fc receptors, or Toll-like receptor 4 in T, B, and is_associated_with::natural killer cells.

Biochemically, caspase-8 was found to enter the complex of the inhibitor of is_associated_with::NF-κB is_associated_with::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 is_associated_with::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.

Interactions
Caspase-8 has been shown to interact with:


 * is_associated_with::BCAP31,
 * BID,
 * is_associated_with::Bcl-2,
 * is_associated_with::CFLAR,
 * is_associated_with::Caspase-10,
 * is_associated_with::Caspase-2,
 * is_associated_with::Caspase-3,
 * is_associated_with::Caspase-6,
 * is_associated_with::Caspase-7,
 * is_associated_with::Caspase-9,
 * is_associated_with::DEDD,
 * is_associated_with::FADD,
 * FasL,
 * FasR,
 * is_associated_with::IFT57,
 * is_associated_with::NOL3,
 * is_associated_with::PEA15,
 * is_associated_with::RIPK1,
 * is_associated_with::TNFRSF10B,  and
 * is_associated_with::TRAF1.