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. Note: This description may include information from UniProtKB.
Molecular Function: peptidase activity; protein binding; hydrolase activity; protein heterodimerization activity; ubiquitin protein ligase binding; cysteine-type endopeptidase activity; endopeptidase activity; death receptor binding; protein complex binding; tumor necrosis factor receptor binding; cysteine-type peptidase activity
Biological Process: caspase activation; cardiac muscle development; positive regulation of I-kappaB kinase/NF-kappaB cascade; macrophage differentiation; positive regulation of proteolysis; apoptosis; protein heterooligomerization; heart development; negative regulation of I-kappaB kinase/NF-kappaB cascade; proteolysis; regulation of apoptosis; response to ethanol; proteolysis involved in cellular protein catabolic process; induction of apoptosis via death domain receptors; angiogenesis; positive regulation of macrophage differentiation; neural tube formation
SS: The number of records in which this modification site was determined using site-specific methods. SS methods include amino acid sequencing, site-directed mutagenesis, modification site-specific antibodies, specific MS strategies, etc.