Caspase-8 is acaspase protein, encoded by theCASP8 gene. It most likely acts uponcaspase-3.CASP8orthologs[5] have been identified in numerousmammals for which complete genome data are available. These unique orthologs are also present inbirds.
TheCASP8 gene encodes a member of thecysteine-aspartic acidprotease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cellapoptosis. Caspases exist as inactiveproenzymes composed of aprodomain, a large proteasesubunit, and a small protease subunit. Activation of caspases requiresproteolytic processing at conserved internal aspartic residues to generate aheterodimeric enzyme consisting of the large and small subunits. This protein is involved in theprogrammed cell death induced byFas and various apoptotic stimuli. The N-terminalFADD-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 fromHuntington disease patients but not in those from normal controls, which implicated the role inneurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined.[6]
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 toALPS, another genetic disease ofapoptosis, with the addition of animmunodeficient phenotype. Thus, the clinical manifestations includesplenomegaly andlymphadenopathy, in addition to recurrent sinopulmonary infections, recurrentmucocutaneousherpesvirus, persistent warts andmolluscum contagiosum infections, andhypogammaglobulinemia. There is sometimes lymphocytic infiltrative disease inparenchymal organs, butautoimmunity is minimal andlymphoma has not been observed in the CEDS patients. CEDS is inherited in an autosomal recessive manner.[7]
The clinical phenotype of CEDS patients represented aparadox since caspase-8 was considered to be chiefly aproapoptoticprotease, that was mainly involved in signal transduction fromTumor 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 inlymphocytes. Further work revealed that caspase-8 was essential for the induction of the transcription factor “nuclear factor κB” (NF-κB) after stimulation throughantigen receptors, Fc receptors, or Toll-like receptor 4 in T, B, andnatural killer cells.[7]
Biochemically, caspase-8 was found to enter the complex of the inhibitor ofNF-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-8zymogen 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]
^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.PMID11406564.
^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.PMID11788820.S2CID10439592.
^Condorelli G, Vigliotta G, Cafieri A, Trencia A, Andalò P, Oriente F, Miele C, Caruso M, Formisano P, Beguinot F (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.PMID10442631.S2CID20510429.
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.PMID11101867.S2CID345769.
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.PMID11772515.S2CID30243363.
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.PMID15578977.
