Selected-GenAtlas references SOURCE GeneCards NCBI Gene Swiss-Prot Orphanet Ensembl
HGNC UniGene Nucleotide OMIM UCSC
Home Page
FLASH GENE
Symbol CASP8 contributors: mct/np - updated : 03-07-2019
HGNC name caspase 8, apoptosis-related cysteine peptidase
HGNC id 1509
Corresponding disease
CASP8D defective lymphocyte activation and apoptosis
Location 2q33.1      Physical location : 202.098.165 - 202.152.434
Synonym name
  • caspase 8, apoptosis-related cysteine protease
  • FADD homologous-like protease
  • caspase 8,initiator
  • ICE-like apoptotic protease 5
  • MORT1-associated CED-3 homolog
  • caspase 8, apoptosis-related cysteine protease
  • MACH-beta-1/2/3/4 protein
  • Synonym symbol(s) FLICE, MACH, MCH5, CAP4, MGC78473, ALPS2B, Casp-8, FLJ17672
    EC.number 3.4.22.36, 3.4.22.61
    DNA
    TYPE functioning gene
    STRUCTURE 54.27 kb     10 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Physical map
    LOC389070 2 LOC389070 FLJ38973 2q33.1 hypothetical protein FLJ38973 FLJ37953 2q33.1 hypothetical protein FLJ37953 FLJ22555 2q33.1 hypothetical protein FLJ22555 DNAPTP6 2q33.2 DNA polymerase-transactivated protein 6 FLJ37818 2q33.2 hypothetical protein FLJ37818 FLJ31322 2q33.2 hypothetical protein FLJ31322 TRIPIN 2q33.2 tripin AOX1 2q33 aldehyde oxidase 1 AOX2 2q33.2 aldehyde oxidase 2 BZW1 2q33 basic leucine zipper and W2 domains 1 LOC391472 2 similar to bA476B13.3 (KIAA0699 protein) CLK1 2q33 CDC-like kinase 1 PPIL3 2q33 peptidylprolyl isomerase (cyclophilin)-like 3 NIF3L1 2q33-q34 NIF3 NGG1 interacting factor 3-like 1 (S. pombe) ORC2L 2q33 origin recognition complex, subunit 2-like (yeast) MGC39518 2q33.2 hypothetical protein MGC39518 NDUFB3 2q31.3 NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3, 12kDa CFLAR 2q33 CASP8 and FADD-like apoptosis regulator CASP10 2q33-q34 caspase 10, apoptosis-related cysteine protease CASP8 2q33-q34 caspase 8, apoptosis-related cysteine protease ALS2CR12 2q33.2 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 12 ALS2CR3 2q33 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 3 ALS2CR2 2q33-q34 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 2 FLJ25351 2q33.2 hypothetical protein FLJ25351 ALS2CR4 2q33 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 4 MPP4 2q33.2 membrane protein, palmitoylated 4 (MAGUK p55 subfamily member 4) ALS2 2q33.2 amyotrophic lateral sclerosis 2 (juvenile) LOC151256 2q33.2 hypothetical LOC151256 ALS2CR7 2q33.2 amyotrophic lateral sclerosis 2 (juvenile) chromosome region, candidate 7 FZD7 2q33 frizzled homolog 7 (Drosophila) FLJ39061 2q33.2 hypothetical protein FLJ39061 LOC339809 2q33.2 KIAA2012 protein UBL1 2q32.3-q33 ubiquitin-like 1 (sentrin) NOP5/NOP58 2q33.2 ubiquitin-like 1 (sentrin) BMPR2 2q33-q34 bone morphogenetic protein receptor, type II (serine/threonine kinase) FLJ38771 LOC130026
    regionally located closely linked to CASP10
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    10 splicing 2914 57.7 496 affected brain from Huntington's patients 1995 8521391
    also called variant A - Mch5 alpha, alpha 4
    10 splicing 2769 55.4 479 - 1995 8521391
  • also called variant B - Mch5 alpha 1
  • lacking one exon and containing an internal additional coding region
  • 9 splicing 2750 53.7 464 - 1995 8521391
  • also called variant F - Mch5 beta, alpha 2
  • a different 5'utr an internal deletion
  • 8 splicing 1123 27.4 235 - 1995 8521391
  • also called variant E - beta 1
  • truncated protein with an unique C terminal
  • lacking two internal coding regions, which leads to a translation frame shift
  • lacking the catalytic site and may interfere with the pro-apoptotic activity of the complex
  • - splicing - 45 395 - 1996 8681376
    also called alpha 3
    - splicing - 25 220 - 1996 8681376
  • also called beta 2
  • lacking the catalytic site and may interfere with the pro-apoptotic activity of the complex
  • - splicing - 30 261 - 1996 8681376
  • also called beta 4
  • lacking the catalytic site and may interfere with the pro-apoptotic activity of the complex
  • 9 splicing 2938 61 538 ubiquitous 2002 11917123
  • also called variant G - 8L
  • interacting at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1
  • containing a N-terminal extension that is required for interaction with the BCAP31 complex
  • 8 splicing 2655 53 464 - -
    also called variant C
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticspleen   highly
     thymus   highly
    Digestiveliver   highly
    Nervousbrain    
    Reproductivemale systemtestis  moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoietic    
    Lymphoid    
    Muscularstriatumskeletal  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticleukocyte
    cell lineage
    cell lines
    fluid/secretion blood
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal (Fas-associating protein with DEATH domain) FADD-MORT like death effector domain
  • a conserved QACXG pentapeptide active site motif
  • a prodomain (inactive proenzyme)
  • a large protease subunit (inactive proenzyme)
  • a small protease subunit (inactive proenzyme)
  • 2 death effector (DED) domains
  • mono polymer heteromer , dimer
    HOMOLOGY
    interspecies homolog to rattus Casp8 (67.80 pc)
    homolog to murine Casp8 (69.57 pc)
    Homologene
    FAMILY
  • cysteine-aspartic acid protease (caspase) family
  • CASP3 subfamily
  • peptidase C14 family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,interspace
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton
    intracellular,nucleus,nucleoplasm
    text stored in the mitochondrial intermembrane space and released into cytosol after appropriate apoptotic stimuli
    basic FUNCTION
  • promoting CD95/APO1/Fas apoptosis via the cleavage of BID, required for lymphocyte activation
  • involved in the programmed cell death induced by Fas and various apoptotic stimuli
  • cleaving and activating CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10
  • may participate in the GZMB apoptotic pathways
  • cleaving ADPRT
  • hydrolyzing the small-molecule substrate, Ac-Asp-Glu-Val-Asp-AMC
  • having an essential role in lymphocyte activation, immune cell homeostasis, and protective immunity
  • involved in the recruitment of the IKK alpha, beta complex, its activation, and the nuclear translocation of NF kappa B
  • with FADD modulate autophagic signaling in a manner vital to T cell clonal expansion
  • modulator of PIK3R1 Rab-GAP activity and endosomal trafficking
  • is necessary for the efficient activation of downstream events associated with epidermal growth factor (EGF) signaling
  • CASP1, CASP8, and calpain are dispensable for IL33 release by macrophages
  • with FADD, have also been implicated in necroptosis
  • involved in the extrinsic death receptor pathway
  • RIPK1 and caspase-8 were recruited to the DDX58 complex after viral infection and served antagonistic regulatory roles
  • an essential executioner of the death receptor (DR) apoptotic pathway
  • catalyzes an essential intermediate step in the ubiquitination and proteasome-mediated degradation of IRF3
  • catalyzes cleavage of IR-3 during dsRNA-dependent signaling
  • CASP8-mediated cleavage and degradation of activated IRF3 is involved in the down-regulation of dsRNA-inducible genes
  • critical function of caspase-8 in regulating intestinal homeostasis and in protecting intestinal epithelial cells (IECs from TNF-induced necroptotic cell death)
  • is a key initiator of apoptotic cell death where it functions as the apical protease in death receptor-mediated apoptosis triggered via the death-inducing signalling complex (DISC)
  • CASP8 plays an essential cell-intrinsic role in innate inflammatory cytokine production during Yersinia infection
  • importance of CASP8 in the development and homeostasis
  • in addition to their role in amyloid processing, CASP8 and its downstream effector CASP3 are involved in synaptic plasticity, learning, memory and control of microglia pro-inflammatory activation and associated neurotoxicity
  • inhibits programmed necrosis by processing CYLD
  • in the presence of CASP1, CASP8 acts as a positive modulator of the NLRP3-dependent CASP1 signaling cascades that drive both IL1B production and pyroptotic death
  • TNFSF10 and CASP8 expression levels were positively correlated with apoptosis in osteosarcoma
  • CASP8 collaborates with CASP11 to drive tissue damage and execution of endotoxic shock
  • cell-death- and inflammation-independent function of RIPK1 and CASP8, promoting faithful chromosome alignment in mitosis and thereby ensuring genome stability
  • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • FAS/FADD/caspase-8 complex is known as the death-inducing signaling complex (DISC)
  • CASP8/CFLAR heterodimer implicated in control of inflammatory cytokines during microbial infection
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • HIP1/ESRRBL1 heterodimer complex
  • CASP8AP2 protein
  • with FADD impact autophagic signaling (both FADD and CASP8 acting in concert to limit general macroautophagy in a number of cell types)
  • CFLAR
  • PEA15
  • ABCF1, AKAP1, CPE, DOPEY1 and GOPC may be targeted specifically by the initiator CASP8 and CASP10 during the early stages of apoptosis
  • interaction between CASP8 and PIK3R1 promotes RAB5A GTP loading, alters endosomal trafficking, and results in the accumulation of RAB5A-positive endosomes at the edge of the cell
  • CYLD is a substrate for CASP8, and caspase 8 cleaves CYLD to generate a survival signal
  • role for TRAF2-dependent CASP8 ubiquitination as a gatekeeper for extrinsic apoptosis activation in mammalian cells
  • TRAF2-mediated ubiquitin shutoff timer that inactivates CASP8 to exert crucial control over cell-extrinsic apoptosis
  • SMAD7 can directly interact with the CASP8 promoter and act as a transcriptional coactivator
  • CASP8 control of death receptor and TLR necrotic death signaling depends on basal catalytic activity that suppresses the RIPK3 kinase pathway
  • evidence for a mechanism to control CASP8-dependent cell death by the atypical cadherin FAT1
  • RIPK1 blocks early postnatal lethality mediated by CASP8 and RIPK3
  • TNFAIP8L2 can regulate TLR4 inflammatory effect and inhibit further amplification of cascade reaction via CASP8
  • TNF-induced apoptosis leads to CASP8-dependent PAWR-cleavage followed by nuclear accumulation of the C-terminal PAWR (132-340) fragment, which then induces apoptosis
  • indirectly RIPK1 regulates likely CASP8 activation, in part via interaction with the ER stress sensor inositol-requiring protein 1 (ERN1)
  • RIPK3 is an unexpected positive regulator of CASP8 activity that promotes IL1B maturation in bone marrow-derived dendritic cells (BMDCs)
  • EPHA7 interacts with CASP8 to induce apoptotic cell signaling
  • CASP8 functions uniquely in macrophages by controlling the response to TLR activation and macrophage polarization in an RIPK-dependent manner
  • MAP3K7 regulates necroptotic signaling as well as CASP8-mediated apoptotic signaling through both NFKB1-dependent and -independent mechanisms
  • essential role for the adaptor protein TRADD in CASP8 activation and necrosome formation triggered by MAP3K7 inhibition
  • CASP10 negatively regulates CASP8-mediated cell death
  • CASP8 is required upstream of both CFLAR and CASP10 and death-inducing signaling complex (DISC) formation critically depends on the scaffold function of CASP8
  • SCAF11 enhanced the activation of CASP8 and extrinsic cell death machinery within the lower small intestine
  • PLK1 is recruited into mitotic ripoptosomes, where PLK1's activity is controlled via RIPK1-dependent recruitment and CASP8-mediated cleavage
  • cell & other
    REGULATION
    activated by HIP1/ESRRBL1 heterodimer complex
    by TNF in mitochondria pathway for apoptosis
    proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits
    Other regulating FAS/TNFR1 induced apoptosis
    ASSOCIATED DISORDERS
    corresponding disease(s) CASP8D
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral       loss of function
    in neuroblastoma
    tumoral somatic mutation      
    mutation 1225_1226delTG might lead to the loss of cell death function and contribute to the pathogenesis of hepatocellular carcinomas
    tumoral somatic mutation     loss of function
    inactivated by somatic mutations in advanced gastric carcinomas
    constitutional       loss of function
    prevented CYLD degradation, resulting in necrotic death
    Susceptibility
  • contribute to an inherited predisposition to SmCC (small cell carcinoma) of the lung
  • to breast cancer
  • to Alzheimer disease
  • Variant & Polymorphism SNP
  • polymorphisms D302H significantly associated with a highly decreased familial breast cancer risk
  • for CASP8 variants, p.K148R and p.I298V, the association remained significant with Alzheimer disease
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • caspase-8-deficient mice exhibit inflammatory skin disorders due to unregulated activation and accumulation of active IRF3