NCBI and Uniprot Product Information
NCBI Description
This 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. [provided by RefSeq, Jul 2008]
Uniprot Description
CASP8: Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death- inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit. Interacts with FADD, CFLAR and PEA15. Isoform 9 interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1. Interacts with TNFAIP8L2. Interacts with human cytomegalovirus/HHV-5 protein vICA/UL36; this interaction inhibits CASP8 activation. Isoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle. Belongs to the peptidase C14A family. 9 isoforms of the human protein are produced by alternative splicing.
Protein type: EC 3.4.22.61; Protease; Apoptosis
Chromosomal Location of Human Ortholog: 2q33-q34
Cellular Component: CD95 death-inducing signaling complex; cytoplasm; cytoskeleton; cytosol; lipid raft; microtubule organizing center; mitochondrial outer membrane; mitochondrion; neuron projection; Noc1p-Noc2p complex; nucleoplasm
Molecular Function: cysteine-type endopeptidase activity; cysteine-type peptidase activity; death receptor binding; peptidase activity; protein binding; protein complex binding; protein heterodimerization activity; tumor necrosis factor receptor binding; ubiquitin protein ligase binding
Biological Process: angiogenesis; apoptosis; B cell activation; caspase activation; cell structure disassembly during apoptosis; cell surface receptor linked signal transduction; heart development; innate immune response; macrophage differentiation; MyD88-independent toll-like receptor signaling pathway; natural killer cell activation; negative regulation of caspase activity; negative regulation of I-kappaB kinase/NF-kappaB cascade; neural tube formation; positive regulation of I-kappaB kinase/NF-kappaB cascade; positive regulation of macrophage differentiation; positive regulation of proteolysis; programmed cell death; protein heterooligomerization; proteolysis; proteolysis involved in cellular protein catabolic process; response to antibiotic; response to cobalt ion; response to cold; response to estradiol stimulus; response to ethanol; response to lipopolysaccharide; stimulatory C-type lectin receptor signaling pathway; T cell activation; toll-like receptor 3 signaling pathway; toll-like receptor 4 signaling pathway; toll-like receptor signaling pathway; tumor necrosis factor-mediated signaling pathway; viral reproduction
Disease: Breast Cancer; Caspase 8 Deficiency; Hepatocellular Carcinoma; Lung Cancer