Alt. symbols: MCH5 | MACH | FLICE | Casp-8

Approved name: caspase 8
Alt. names: caspase 8, apoptosis-related cysteine protease, caspase 8, apoptosis-related cysteine peptidase

Location: 2q33.1: 201233443 - 201361836 (+)
Gene type: protein_coding, 25 transcripts.

Scores: LoFtool: 0.274000 | pLI: 0.00484502 | LOEUF: 0.811

HGNC: 1509

NCBI: 841, RefSeq: NG_007497.1

Ensembl: ENSG00000064012.24

LRG_34 | Status: public

OMIM: 601763

Expression | ProteinAtlas

CASP8 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 the 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.

Biallelic missense, nonsense, frameshift, and splice site mutations, as well as copy number changes, in CASP8 can result in an autosomal recessive form of autoimmune lymphoproliferative syndrome (ALPS), namely type IIB [MIM:607271]. ALPSIIB is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes. Defective activation of T-lymphocytes, B-lymphocytes, and natural killer cells leads to immunodeficiency characterized by recurrent sinopu lmonary and HSV infections and poor vaccine responses. Clinically, gastrointestinal inflammation that may manifest as early onset inflammatory bowel disease and multiorgan lymphocytic infiltration and granulomas have been reported (PMID: 30267714, 30337362, PMID: 25814141). Tan et al. (2015) has also suggested that CASP8 polymorphisms may also contribute to increased susceptibility to ALPS development (PMID: 26690594). Somatic mutations have been associated with protection against breast and lung cancers and with development of hepatocellular carcinoma [MIM:114550]. [Load More]