Caspase 8

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

CASP8
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1F9E, 1I4E, 1QDU, 1QTN, 2C2Z, 2FUN, 2K7Z, 2Y1L, 3H11, 3KJN, 3KJQ, 4JJ7, 4PRZ, 4PS1, 4ZBW
Identifiers
Aliases	CASP8, ALPS2B, CAP4, Casp-8, FLICE, MACH, MCH5, caspase 8
External IDs	OMIM: 601763; MGI: 1261423; HomoloGene: 7657; GeneCards: CASP8; OMA:CASP8 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) Band 2q33.1 Start 201,233,443 bp End 201,287,711 bp
Gene location (Mouse) Chr. Chromosome 1 (mouse) Band 1 C1.3|1 29.19 cM Start 58,834,533 bp End 58,886,662 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte blood granulocyte buccal mucosa cell bone marrow cells spleen lymph node appendix epithelium of colon rectum Top expressed in jejunum duodenum ileum subcutaneous adipose tissue parotid gland lymph node stroma of bone marrow spleen endothelial cell of lymphatic vessel embryonic cell More reference expression data BioGPS More reference expression data
Gene ontology Molecular function death effector domain binding cysteine-type peptidase activity cysteine-type endopeptidase activity involved in apoptotic signaling pathway scaffold protein binding protein binding identical protein binding cysteine-type endopeptidase activity involved in apoptotic process cysteine-type endopeptidase activity hydrolase activity ubiquitin protein ligase binding peptidase activity cysteine-type endopeptidase activity involved in execution phase of apoptosis death receptor binding tumor necrosis factor receptor binding protein-containing complex binding Cellular component cell body cytosol CD95 death-inducing signaling complex ripoptosome nucleoplasm mitochondrial outer membrane death-inducing signaling complex membrane raft neuron projection cytoskeleton cytoplasm mitochondrion nucleus protein-containing complex Biological process regulation of apoptotic process response to estradiol activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway response to antibiotic regulation of tumor necrosis factor-mediated signaling pathway positive regulation of macrophage differentiation cellular response to organic cyclic compound natural killer cell activation negative regulation of I-kappaB kinase/NF-kappaB signaling TRAIL-activated apoptotic signaling pathway proteolysis macrophage differentiation TRIF-dependent toll-like receptor signaling pathway response to tumor necrosis factor B cell activation cell surface receptor signaling pathway response to lipopolysaccharide cellular response to mechanical stimulus activation of cysteine-type endopeptidase activity positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway death-inducing signaling complex assembly positive regulation of proteolysis positive regulation of I-kappaB kinase/NF-kappaB signaling apoptotic signaling pathway response to cold regulation of extrinsic apoptotic signaling pathway via death domain receptors viral process response to ethanol response to cobalt ion activation of cysteine-type endopeptidase activity involved in apoptotic process proteolysis involved in cellular protein catabolic process syncytiotrophoblast cell differentiation involved in labyrinthine layer development nucleotide-binding oligomerization domain containing signaling pathway T cell activation suppression by virus of host cysteine-type endopeptidase activity involved in apoptotic process apoptotic process extrinsic apoptotic signaling pathway negative regulation of extrinsic apoptotic signaling pathway via death domain receptors regulation of necroptotic process execution phase of apoptosis toll-like receptor 3 signaling pathway positive regulation of neuron death extrinsic apoptotic signaling pathway via death domain receptors positive regulation of interleukin-1 beta production Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 841 12370 Ensembl ENSG00000064012 ENSMUSG00000026029 UniProt Q14790 O89110 RefSeq (mRNA) NM_001080124 NM_001080125 NM_001228 NM_033355 NM_033356 NM_033357 NM_033358 NM_001372051 NM_001080126 NM_001277926 NM_009812 RefSeq (protein) NP_001073593 NP_001073594 NP_001219 NP_203519 NP_203520 NP_203522 NP_001358980 NP_001073595 NP_001264855 NP_033942 Location (UCSC) Chr 2: 201.23 – 201.29 Mb Chr 1: 58.83 – 58.89 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

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.

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.

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.

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.

Interactions

Caspase-8 has been shown to interact with:

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

Additional photos

Signaling pathway of TNF-R1. Dashed grey lines represent multiple steps Overview of signal transduction pathways involved in apoptosis.

See also

• Caspase
• FADD
• The Proteolysis Map

Further reading

• 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

• The MEROPS online database for peptidases and their inhibitors: C14.009
• 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.