Alternative titles; symbols
HGNC Approved Gene Symbol: CASP8
SNOMEDCT: 722290008;
Cytogenetic location: 2q33.1 Genomic coordinates (GRCh38): 2:201,233,463-201,287,711 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q33.1 | ?Caspase 8 lymphadenopathy syndrome | 607271 | Autosomal recessive | 3 |
| {Breast cancer, protection against} | 114480 | Autosomal dominant; Somatic mutation | 3 | |
| {Lung cancer, protection against} | 211980 | Autosomal dominant; Somatic mutation | 3 | |
| Hepatocellular carcinoma, somatic | 114550 | 3 |
A cascade of protease reactions is believed to be responsible for the apoptotic changes observed in mammalian cells undergoing programmed cell death. This cascade involves members of the aspartate-specific cysteine proteases of the ICE/CED3 (CASP1; 147678) family, also known as the caspase family.
Fernandes-Alnemri et al. (1996) identified the novel gene MCH5 when they found a human EST sequence with significant homology to the newly identified cysteine protease MCH4 (601762). They used PCR to clone a cDNA of the MCH5 gene from a Jurkat T-cell cDNA library. Sequence analysis revealed that it encodes a polypeptide of 496 amino acids with greatest homology to MCH4. The authors found that MCH4 and MCH5 both contain the active site pentapeptide QACQG instead of the QACRG present in all other known members of the family. Furthermore, the authors found that the sequences of MCH4 and MCH5 contain Fas-associating protein with death domain (FADD; 602457)-like domains, suggesting possible interaction with FADD. Fernandes-Alnemri et al. (1996) stated that MCH5, like other members of the ICE/CED3 family, forms an active protease only after cleavage of its proenzyme into 2 subunits which dimerize to form the active enzyme.
Using MORT1 (FADD) in a yeast 2-hybrid screen of a B-cell cDNA library, Boldin et al. (1996) cloned several splice variants of CASP8, which they called MACH. The isoforms could be divided into 2 main subgroups. All isoforms share a common 182-amino acid N-terminal region, including 2 MORT modules (i.e., death effector domains, or DEDs), but they have different C termini. Subgroup alpha isoforms have C termini containing a CED3/ICE homology domain that contains the catalytic site and the substrate-binding pocket, while subgroup beta isoforms are truncated and lack the CED3/ICE homology domain. The longest isoform, MACH-alpha-1, encodes a deduced 479-amino acid protein. The CED3/ICE domain of MACH-alpha-1 shares 41% and 34% identity with the homologous regions in CPP32 (CASP3; 600636) and C. elegans CED3, respectively. Northern blot analysis detected MACH transcripts ranging in size between 2.85 and 3.5 kb in all tissues examined, with highest levels in resting peripheral blood mononuclear leukocytes and lowest levels in testis and skeletal muscle.
Eckhart et al. (2001) identified several CASP8 splice variants that preferentially use a distant splice donor site at the 3-prime end of exon 8. Use of this distant site, which they called exon 8b, results in mRNAs with truncated open reading frames. RT-PCR indicated equal expression of both mRNA species in tonsil, spleen, bone marrow, thymus, and lymph nodes. Peripheral blood leukocytes, heart, and epidermis predominantly expressed mRNA containing exon 8b, as did a promyelocytic cell line and a T-cell line. Liver and nearly all immortalized cell lines, as well as primary endothelial cells, fibroblasts, and keratinocytes, expressed mRNA lacking the 8b extension.
Using fluorogenic peptide substrates corresponding to a sequence within the nuclear protein PARP (173870), Boldin et al. (1996) confirmed that MACH-alpha-1 is a thiol protease. By site-directed mutagenesis, they identified cys360 as the catalytic cysteine. Using mutation analysis, Boldin et al. (1996) determined that MACH binds to the N terminus of MORT1. They also found that it self-associates, but it does not interact directly with FAS/APO1 (TNRFSF6; 134637). Transfection of human embryonic kidney cells and breast carcinoma cells with MACH-alpha-1 or MACH-alpha-2 resulted in massive cell death.
Muzio et al. (1996) determined that CASP8, which they called FLICE, interacts with wildtype FADD but not with FADD lacking the DED. They also determined that granzyme B (GZMB; 123910) can remove the prodomain and generate the active p20/p10 dimeric cysteine protease. Cleavage of PARP by CASP8 resulted in the appearance of signature apoptotic fragments. Transfection and overexpression of CASP8 in transfected breast cancer cells resulted in apoptosis.
Expression of cDNAs that encode truncated polypeptides containing mostly expanded polyglutamine repeats, but not of those that encode the corresponding full-length proteins, has been shown to induce cell death by apoptosis. Such truncated proteins have been shown to form aggregates or inclusions (Ikeda et al., 1996). Sanchez et al. (1999) studied the role of caspases in polyglutamine-induced cell death in established cultures of primary cortical, striatal, and cerebellar neurons from embryonic day 17 rat embryos, transfected with an expression construct encoding truncated ataxin-3 that contained 79 glutamine (Q79) residues. The authors showed that the apoptosis inhibitors Bcl2, CrmA, and a truncated Fas/APO1-associated death domain protein (FADD DN) inhibited polyglutamine repeat-induced neuronal cell death. A mutant Jurkat cell line specifically lacking caspase-8 was resistant to polyglutamine-induced cell death. Cells transfected with Q79 showed insoluble inclusions. Caspase-8 was recruited and activated by these Q79 inclusions. Western blot analysis revealed the presence of activated caspase-8 in the insoluble fraction of affected brain regions from Huntington disease (143100) patients but not in those from controls. The authors suggested that caspase-8 has an essential role in Huntington-related neurodegenerative diseases.
Eckhart et al. (2001) found that different CASP8 isoforms were expressed in resting and activated lymphocytes. Activation of lymphocytes shifted the expression from mRNA species containing an exon 8b extension to mRNAs that lack it. Differentiation in a promyelocytic cell line was associated with the opposite shift, from mRNAs containing the shorter exon 8 to mRNAs that include the exon 8b extension.
Gervais et al. (2002) found that HIP1 (601767) binds to the HIP1 protein interactor (HIPPI; 606621), which has partial sequence homology to HIP1 and similar tissue and subcellular distribution. The availability of free HIP1 is modulated by polyglutamine length within huntingtin (613004), with disease-associated polyglutamine expansion favoring the formation of proapoptotic HIPPI-HIP1 heterodimers. This heterodimer can recruit procaspase-8 into a complex of HIPPI, HIP1, and procaspase-8, and launch apoptosis through components of the extrinsic cell death pathway. Gervais et al. (2002) proposed that huntingtin polyglutamine expansion liberates HIP1 so that it can form a caspase-8 recruitment complex with HIPPI, possibly contributing to neuronal death in Huntington disease.
Yu et al. (2004) defined a novel molecular pathway in which activation of the receptor-interacting protein (RIP, or RIPK1; 603453), a serine-threonine kinase, and Jun amino-terminal kinase (601158) induced cell death with the morphology of autophagy. Autophagic death required the genes ATG7 (GSA7; 608760) and beclin-1 (604378) and was induced by caspase-8 inhibition. Yu et al. (2004) cautioned that clinical therapies involving caspase inhibitors may arrest apoptosis but also have the unanticipated effect of promoting autophagic cell death.
Ricci-Vitiani et al. (2004) found that human neural progenitor cells (NPCs) lacked expression of CASP8, and that absence of CASP8 provided resistance to DR ligand-induced apoptosis. Even in the presence of inflammatory cytokines, which induced CASP8 expression, DRs were unable to generate death signals in primitive neural cells. Exogenous expression of CASP8 did not trigger DR-induced apoptosis in NPCs, suggesting that, in addition to absence of CASP8, NPCs had a second mechanism to protect them from DR-induced cell death. Further analysis identified high expression of PEA15 (603434) in NPCs as another level of protection, as PEA15 localized in the death-inducing signaling complex and blocked CASP8 recruitment and activation. Although CASP8 was absent in both adult and embryonic NPCs, immunoblot analysis and RNase protection assays revealed that CASP8 levels increased dramatically during neuronal differentiation, indicating that the presence of CASP8 in neurons is a developmentally regulated process.
Poulaki et al. (2005) found that human retinoblastoma (RB1; 614041) cell lines were resistant to death receptor (see DR5; 603612)-mediated apoptosis because of a deficiency of CASP8 expression secondary to epigenetic gene silencing by overmethylation. Treatment with a demethylating agent restored CASP8 expression and sensitivity to apoptosis.
Su et al. (2005) showed that caspase-8 deficiency (607271) in humans and mice specifically abolishes activation of the transcription factor NF kappa-B (164011) after stimulation through antigen receptors, Fc receptors, or Toll-like receptor-4 (TLR4; 603030) in T, B, and natural killer cells. Caspase-8 also causes the alpha-beta complex of the inhibitor of NF-kappa-B kinase (IKK; 600644 and 300248, respectively) to associate with the upstream BCL10 (603517)-MALT1 (604860) adaptor complex. Recruitment of the IKK-alpha,beta complex, its activation, and the nuclear translocation of NF-kappa-B require enzyme activity of full-length caspase-8. Su et al. (2005) concluded that their findings explained the paradoxical association of defective apoptosis and combined immunodeficiency in human caspase-8 deficiency.
Stupack et al. (2006) showed that suppression of caspase-8 expression occurs during the establishment of neuroblastoma (256700) metastases in vivo, and that reconstitution of caspase-8 expression in deficient neuroblastoma cells suppressed their metastases. Caspase-8 status was not a predictor of primary tumor growth; rather, caspase-8 selectively potentiated apoptosis in neuroblastoma cells invading the collagenous stroma at the tumor margin. Apoptosis was initiated by unligated integrins (see 605025) by means of a process known as integrin-mediated death. Loss of caspase-8 or integrin rendered the cells refractory to integrin-mediated death, allowed cellular survival in the stromal microenvironment, and promoted metastases. Stupack et al. (2006) concluded that these findings define caspase-8 as a metastasis suppressor gene that, together with integrins, regulates the survival and invasive capacity of neuroblastoma cells.
Using immunofluorescence analysis, Barbero et al. (2008) showed that CASP8 was recruited to lamella of NB7 neuroblastoma cells and enhanced cell migration. Mutation analysis revealed that the catalytic domain of CASP8 was sufficient for recruitment to lamella, but that its caspase catalytic activity was not necessary. The linker region in the CASP8 catalytic domain acted as an SRC (190090) homology-2 (SH2) binding site, with a critical residue, tyr380, phosphorylated during integrin-mediated cell adhesion. Tyr380 phosphorylation affected CASP8 interaction with SH2 domains, localization to lamella, and promotion of cell migration.
Oberst et al. (2011) showed that development of caspase-8-deficient mice is completely rescued by ablation of receptor-interacting protein kinase-3 (RIPK3; 605817). Adult animals lacking both caspase-8 and Ripk3 displayed a progressive lymphoaccumulative disease resembling that seen with defects in Cd95 or Cd95 ligand (FASL; 134638), and resisted the lethal effects of Cd95 ligation in vivo. Oberst et al. (2011) found that caspase-8 prevents RIPK3-dependent necrosis without inducing apoptosis by functioning in a proteolytically active complex with CFLAR (603599) and that this complex is required for the protective function.
Kaiser et al. (2011) found that Ripk3 is responsible for the midgestational death of Casp8-deficient embryos. Remarkably, Casp8-null/Rip3-null-double mutant mice were viable and matured into fertile adults with a full immune complement of myeloid and lymphoid cell types. These mice seemed immunocompetent but developed lymphadenopathy by 4 months of age marked by accumulation of abnormal T cells in the periphery, a phenotype reminiscent of mice with Fas deficiency. Thus, Kaiser et al. (2011) concluded that Casp8 contributes to homeostatic control in the adult immune system; however, RIPK3 and CASP8 are together completely dispensable for mammalian development.
Burguillos et al. (2011) showed that the orderly activation of caspase-8 and caspase-3/7 (600636/601761), known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C-delta (PPKCD; 176977)-dependent pathway. Burguillos et al. (2011) found that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. The authors observed that these caspases are activated in microglia in the ventral mesencephalon of Parkinson disease (168600) and the frontal cortex of individuals with Alzheimer disease (104300). Burguillos et al. (2011) concluded that caspase-8 and caspase-3/7 are involved in regulating microglia activation, and suggested that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
Gunther et al. (2011) demonstrated a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IECs) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8-delta-IEC) spontaneously developed inflammatory lesions in the terminal ileum were highly susceptible to colitis. These mice lacked Paneth cells and showed reduced numbers of goblet cells, indicating dysregulated antimicrobial immune cell functions of the intestinal epithelium. Casp8-delta-IEC mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumor necrosis factor-alpha (TNFA; 191160), was associated with increased expression of RIP3 and could be inhibited on blockade of necroptosis. Lastly, Gunther et al. (2011) identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Gunther et al. (2011) concluded that their data demonstrated a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IECs from TNFA-induced necroptotic cell death.
O'Donnell et al. (2011) identified CYLD (605018) as the key substrate for CASP8 to inhibit programmed necrosis. Analysis with mouse embryonic fibroblasts (MEFs) showed that Cyld was essential for necrotic cell death. Upon TNF stimulation, CASP8 proteolytically cleaved CYLD at the carboxyl end of asp215 to generate a survival signal and block necrosis in various cell types. In contrast, loss of CASP8 blocked proteolytic degradation of CYLD and triggered programmed necrosis. Mutation of asp215 was sufficient to convert the prosurvival response to TNF-induced necrosis, even in the presence of CASP8. Cleavage by CASP8 removed the deubiquitinase domain of CYLD and prevented CYLD from deubiquitinating downstream molecules, such as RIPK1, thereby affecting its interactions with signaling partners and resulting in a switch from a prosurvival NEMO (IKBKG; 300248)-RIPK1 complex to a pronecrotic RIPK1-FADD complex.
Heger et al. (2018) showed that OTULIN (615712) promotes rather than counteracts LUBAC (see 610924) activity by preventing its autoubiquitination with linear polyubiquitin. Thus, knockin mice that express catalytically inactive Otulin, either constitutively or selectively in endothelial cells, resembled Lubac-deficient mice and died midgestation as a result of cell death mediated by Tnfr1 (191190) and the kinase activity of Ripk1. Inactivation of Otulin in adult mice also caused proinflammatory cell death. Accordingly, embryonic lethality and adult autoinflammation were prevented by the combined loss of cell death mediators: Casp8 for apoptosis and Ripk3 for necroptosis. Unexpectedly, Otulin mutant mice that lacked Casp8 and Ripk3 died in the perinatal period, exhibiting enhanced production of type I interferon that was dependent on Ripk1. Heger et al. (2018) concluded that their results indicated that OTULIN and LUBAC function in a linear pathway, and highlighted a previously unrecognized interaction between linear ubiquitination, regulators of cell death, and induction of type I interferon.
Using knockout mice, Mandal et al. (2018) showed that proapoptotic Casp8 and propyroptotic Casp11 (602664) were essential for lethal lipopolysaccharide (LPS) shock and E. coli sepsis. Casp8 and Casp11 were not required for initiation of LPS shock, which was triggered by a distinct hematopoietic initiator compartment. Small intestine and spleen were the critical target organs affected by Casp8-dependent LPS shock. Casp8 and Casp11 dictated ileal inflammation and both contributed to LPS-driven systemic inflammation. However, neither Casp8 nor Casp11 was individually sufficient for shock, and both Casp8 and Casp11 had to collaborate to execute inflammatory tissue injury underlying endotoxemia. The collaboration was driven by Tnf and type I IFN for the execution of LPS shock, but it was independent of Ripk1 activity. Casp11 enhanced activation of Casp8, but Casp11-dependent pyroptosis was independent of Casp8.
Newton et al. (2019) showed that knockin mice that express catalytically inactive caspase-8 carrying the C362A mutation die as embryos owing to MLKL (615153)-dependent necroptosis, similar to caspase-8-deficient mice. Thus, caspase-8 must cleave itself, other proteins, or both to inhibit necroptosis. Mice that express caspase-8(D212A/D218A/D225A/D387A), which cannot cleave itself, were viable, as were mice that express cFLIP (603599) or CYLD proteins that had been mutated to prevent cleavage by caspase-8. By contrast, mice that express RIPK1(D325A), in which the caspase-8 cleavage site asp325 had been mutated, died midgestation. Embryonic lethality was prevented by inactivation of RIPK1, loss of TNFR1, or loss of both MLKL and the caspase-8 adaptor FADD, but not by loss of MLKL alone. Thus, RIPK1(D325A) appeared to trigger cell death mediated by TNF, the kinase activity of RIPK1, and FADD-caspase-8. Accordingly, dying endothelial cells that contained cleaved caspase-3 were abnormally abundant in yolk sacs of Ripk1(D325A/D325A) embryos. Heterozygous Ripk1(D325A/+) cells and mice were viable, but were also more susceptible to TNF-induced cell death than were wildtype cells or mice. Newton et al. (2019) concluded that their data showed that asp325 of RIPK1 is essential for limiting aberrant cell death in response to TNF, consistent with the idea that cleavage of RIPK1 by caspase-8 is a mechanism for dismantling death-inducing complexes.
Newton et al. (2019) showed that catalytically inactive Casp8 with the C362A mutation induced formation of Asc (PYCARD; 606838) specks and Casp1-dependent cleavage of Gsdmd (617042), Casp3, and Casp7 in Mlkl-deficient mouse intestine around embryonic day-18. Analysis of various mouse mutants showed that Casp1 and its adaptor Asc, upregulation of Casp11 in intestine, and a necroptosis-independent function of Ripk3 all contributed to lethality in Mlkl -/- mice homozygous for the Casp8 C362A mutation. Newton et al. (2019) concluded that their data revealed crosstalk between the apoptosis, necroptosis, and pyroptosis cell death pathways. The findings suggested that CASP1-dependent cell death also guards against inhibition of CASP8, serving as a backup mechanism for cell death when necroptosis is compromised. The authors suggested that this crosstalk may have evolved as a defence against viruses that encode inhibitors of both CASP8 and protein interactions that promote MLKL-dependent necroptosis.
Fritsch et al. (2019) showed that expression of catalytically inactive Casp8 with a C362S mutation caused embryonic lethality in mice by inducing necroptosis and pyroptosis. Similar to Casp8-null mice, mouse embryos homozygous for the C362S mutation died after endothelial cell necroptosis leading to cardiovascular defects. Mlkl deficiency rescued the cardiovascular phenotype but caused perinatal lethality in homozygous Casp8-C362S mice, indicating that C362S caused necroptosis-independent death at later stages of embryonic development. Specific loss of Casp8 catalytic activity in intestinal epithelial cells induced intestinal inflammation similar to that of intestinal epithelial cell-specific Casp8-knockout mice. Inhibition of necroptosis by deletion of Mlkl severely aggravated intestinal inflammation and caused premature lethality in mice with loss of Casp8 catalytic activity in intestinal epithelial cells. Expression of Casp8-C362S triggered formation of Asc specks, activation of Casp1, and secretion of Il1-beta. Loss of Asc or Casp1 rescued embryonic lethality and premature death in Mlkl-null mice homozygous for Casp8-C362S, indicating that inflammasome activation promotes Casp8-C362S-mediated tissue pathology when necroptosis is blocked. Fritsch et al. (2019) concluded that CASP8 represents the molecular switch that controls apoptosis, necroptosis, and pyroptosis and prevents tissue damage during embryonic development and adulthood.
Using genetic approaches, Tummers et al. (2020) showed that mice expressing oligomerization-deficient or noncleavable mutant Casp8 did not develop lymphoproliferative (LPR) disease, as Casp8 mutants blocked necroptosis during embryogenesis and made them relatively resistant to Cd95-mediated apoptosis. Deletion of the necroptosis effector Mlkl from mice expressing noncleavable mutant Casp8 revealed that Casp8 was able to mediate lethal, proinflammatory cytokine production in response to Cd95 ligation. As a result, noncleavable Casp8 induced an inflammatory environment, but it was controlled by the ability of precursors of Cd3 (see 186740)-positive/B220 (PTPRC; 151460)-positive cells to undergo necroptotic death, thereby preventing lethal inflammation and protecting mice from death. Inflammation in mice expressing noncleavable Casp8 and lacking Mlkl was prevented by ablation of 1 allele of Fasl, Fadd, or Ripk1, but full ablation of Fadd exacerbated inflammation and caused Casp1-dependent lethality. These results indicated that the inflammatory phenotype was dependent on the FADDosome, whereas the inflammatory role of Casp8 was Fadd-independent, and Fadd suppressed a proinflammatory function of noncleavable mutant Casp8. Further analysis with intestinal epithelial cells revealed that noncleavable Casp8 interacted with Asc and induced its oligomerization in the absence of Fadd. This interaction was blocked by Fadd and the ability of Casp8 to self-cleave. Furthermore, suppression of this inflammasome activation appeared to be required for survival of mice expressing noncleavable mutant Casp8.
Muendlein et al. (2020) showed that deficiency of the long form (L) of cFLIP (cFLIP(L)) promotes mitochondrial complex II (see 600857) formation driving pyroptosis and the secretion of IL1-beta (147720) in response to LPS alone. cFLIP(L) deficiency was sufficient to drive complex II formation in response to LPS. RIP1 and CASP8 recruitment to FADD occurred as early as 2 hours after LPS addition. Muendlein et al. (2020) found that in macrophages and perhaps in other cells if levels of cFLIP(L) are sufficiently high, CASP8 activation and pyroptosis are inhibited. When cFLIP(L) levels are low, CASP8 homodimers form readily. Fully active CASP8 cleaves and activates distant targets, and LPS-activated macrophages rapidly undergo pyroptosis and secrete IL1-beta. CASP3, CASP7, and CASP9 (602234) are dispensable for CASP8-driven pyroptosis in the absence of cFLIP(L). Instead, CASP8 likely directly activates GSDMD to drive pyroptosis and the NLRP3 (606416) inflammasome to drive IL1-beta maturation and release.
By treating mouse bone marrow-derived macrophages (BMDMs) with IFN-gamma (147570) followed by the TLR4 agonist LPS, Simpson et al. (2022) found that IFN-gamma activated macrophages and triggered cell death via TLR signaling and Fasl expression. Knockout analysis revealed that efficient IFN-gamma/LPS-induced cell death required caspase-8 and the mitochondrial apoptosis effector proteins Bax (600040) and Bak (BAK1; 600516). Activation of Bax and Bak was not triggered by caspase-8 cleavage of its substrate Bid (601997). Instead, caspase-8 mediated transcriptional programming in macrophages to increase proapoptotic Noxa (PMAIP1; 604959) and reduce prosurvival Bcl2 (151430), thereby reducing prosurvival proteins Mcl1 (159552) and A1 to facilitate Bax/Bak activation and subsequent apoptotic cell death upon stimulation with IFN-gamma and LPS. Caspase-8 enzymatic activity was required for IFN-gamma/LPS-mediated activation of Bax/Bak and subsequent apoptotic cell death. Bax/Bak activation resulted in irreversible damage to mitochondria and caused cell death even when the functions of other downstream caspases were eliminated. Treatment with IFN-gamma/LPS induced robust expression of iNos (NOS2; 163730) and generation of nitric oxide in macrophages, upstream of Bax/Bak activation and cell death. However, toxicity of nitric oxide was not the direct cause of cell death. Instead, iNos expression played a role in reducing Mcl1 and A1 to sensitize macrophages for Bax/Bak activation and mitochondrial apoptosis. In agreement, both iNos and caspase-8 contributed to disease severity of SARS-CoV-2 infection in mice, as deletion of iNos or caspase-8 limited SARS-CoV-2-induced disease, whereas caspase-8 caused lethality through hemophagocytic lymphohistiocytosis independently of iNos.
By genomic sequence analysis, Varfolomeev et al. (1998) determined that the CASP8 gene contains 8 exons. Hadano et al. (2001) determined that the CASP8 gene contains 13 exons and spans 51.2 kb.
By fluorescence in situ hybridization (FISH), Kischkel et al. (1998) mapped the CASP8 gene to human chromosome 2q33-q34 and mouse chromosome 1B-proximal C. This mapping further extended the known homology of synteny between these regions of human chromosome 2 and mouse chromosome 1. By FISH, Grenet et al. (1999) also mapped the CASP8 gene to 2q33-q34. They noted that CASP10 (601762), whose product is closely related to that of CASP8, has been mapped to the same location, indicating that the 2 genes evolved by tandem duplication.
Liu et al. (2002) identified a naturally occurring deletion of leu62 within the first DED of CASP8 in A431 human vulva squamous carcinoma cells. This deletion resulted in defective CASP8-dependent apoptosis. Unlike wildtype CASP8, CASP8 lacking leu62 failed to form oligomers with wildtype CASP8 and failed to interact with FADD. The mutation did not affect proteolytic activation by granzyme B, nor did it affect catalytic activity against PARP.
In 2 affected sibs from a consanguineous family with caspase-8 deficiency (607271), Chun et al. (2002) identified a homozygous mutation in the CASP8 gene (601763.0001). The patients had defects in the activation of T and B lymphocytes and natural killer cells, which led to immunodeficiency.
Soung et al. (2005) analyzed the entire coding region of the CASP8 gene in 69 hepatocellular carcinomas (HCC; 114550), 2 with low-grade dysplastic nodule (LGDN), 2 with high-grade dysplastic nodule (HGDN), and 65 without dysplastic nodules, and detected a total of 9 somatic mutations (13%). All 9 mutations were an identical 2-bp deletion (nucleotides 1225-1226; 601763.0002), which was predicted to result in frameshift and premature termination of amino acid synthesis in the p10 protease subunit. The change was detected both in HCC and in LGDN lesions, suggesting that CASP8 mutation may be involved in the early stage of HCC carcinogenesis. Soung et al. (2005) found that expression of the tumor-derived caspase-8 mutant in cells abolished cell death activity of caspase-8.
Cox et al. (2007) reported the findings of the Breast Cancer Association Consortium (BCAC), which had been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. They genotyped 9 SNPs for which there was some prior evidence of an association with breast cancer (114480). They included data from 9 to 15 studies, comprising 11,391 to 18,290 cases and 14,753 to 22,670 controls. They found evidence of a protective association with breast cancer for a D302H polymorphism in CASP8 (601763.0003), and weaker evidence for an L10P SNP in the TGFB1 gene (190180.0007). These results demonstrated that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies.
Caspases are important in the life and death of immune cells and therefore influence immune surveillance of malignancies. Sun et al. (2007) tested whether genetic variants in CASP8, CASP10, (601762), and CFLAR (603599), 3 genes important for death receptor-induced cell killing residing in tandem order on chromosome 2q33, are associated with cancer susceptibility. Using a haplotype-tagging SNP approach, they identified a 6-nucleotide deletion (-652 6N del) variant in the CASP8 promoter (601763.0004) associated with decreased risk of lung cancer. The deletion destroyed a binding site for stimulatory protein-1 (SP1; 189906) and decreased transcription. Biochemical analyses showed that T lymphocytes with the deletion variant had lower caspase-8 activity and activation-induced cell death upon stimulation with cancer cell antigens. Case-control analyses of 4,995 individuals with cancer and 4,972 controls in a Chinese population showed that this genetic variant is associated with reduced susceptibility to multiple cancers, including lung, esophageal, gastric, colorectal, cervical, and breast cancers, acting in an allele dose-dependent manner. The results supported the hypothesis that genetic variants influencing immune status modify cancer susceptibility. Haiman et al. (2008) did not find an association between this SNP and breast (114480), colorectal (114500), or prostate (176807) cancer among 2,098, 1,139, and 2,825 patients, respectively. The study included patients in Hawaii and California of various ethnic groups.
Varfolomeev et al. (1998) generated mice deficient in Casp8 by disrupting exons 1 and 2, which encode the N-terminal death effector domains (DEDs) that interact with MORT1/FADD. Whereas wildtype and heterozygous mice appeared normal, no homozygous mutant mice survived beyond approximately embryonic day 13.5. Histopathologic analysis revealed marked abdominal hyperemia with erythrocytosis in the liver, major blood vessels, capillaries, and other organs. Cardiac ventricular musculature was thin and similar to early mesenchyme. Colony forming assays showed that hemopoietic precursor cells were markedly reduced in the mutant mice. Immunoprecipitation and Western blot analysis indicated that fibroblasts from mutant mice responded normally to the noncytocidal effects of tumor necrosis factor receptor (TNFR; 191190) and death receptor-3 (DR3, or TNFRSF12; 603366) stimulation, whereas wildtype fibroblasts were killed by TNF treatment or FAS cross-linking. Agents such as ultraviolet irradiation and protein kinase inhibitors were lethal for mutant and normal fibroblasts. Varfolomeev et al. (1998) concluded that CASP8 is necessary for death induction by receptors of the TNF/nerve growth factor (see NGFR; 162010) family and is vital in embryonal development.
Zender et al. (2003) evaluated the efficacy of small interfering RNA (siRNA) in vivo in different mouse models with acute liver failure. They directed 21-nucleotide siRNAs against caspase-8, which is a key enzyme in death receptor-mediated apoptosis. Systemic administration of caspase-8 siRNA resulted in inhibition of caspase-8 gene expression in the liver, therefore preventing CD95-mediated apoptosis. Protection of hepatocytes by caspase-8 siRNA significantly attenuated acute liver damage induced by CD95 antibody or by adenovirus expressing FAS ligand. In a clinical situation, siRNAs would most likely be administered after the onset of acute liver failure. Therefore, Zender et al. (2003) injected caspase-8 siRNA at a time during experimentally-induced liver failure with already elevated liver transaminases. Improvement of survival due to RNA interference was significant even when caspase-8 siRNA was applied during ongoing acute liver failure.
Salmena and Hakem (2005) used the Cre/lox recombinase system to generate mice lacking Casp8 only in T cells (Tcasp8 -/- mice). Tcasp8 -/- mice developed an age-dependent lethal lymphoproliferative and lymphoinfiltrative immune disorder characterized by lymphoadenopathy, splenomegaly, and T-cell infiltrates in lung, liver, and kidney. Although there was lymphopenia in young Tcasp8 -/- mice, peripheral T cells in old Tcasp8 -/- mice proliferated in the absence of infection or stimulation. Salmena and Hakem (2005) proposed that Tcasp8 -/- mice may serve as a model of human CASP8 deficiency and that CASP8 in T cells is required for lymphocyte homeostasis.
To define the contribution of reduced caspase-8 to a wound healing response, Lee et al. (2009) generated an epidermal knockout of caspase-8. By postnatal day 10 the conditional knockout mouse had flaky skin throughout its body, was slightly runted, and its epidermis was dramatically thickened. Lee et al. (2009) found that even though caspase-8 is normally expressed in the granular layer, it was the basal and spinous layers that were markedly expanded in the knockout epidermis. Lee et al. (2009) demonstrated that the loss of epidermal caspase-8, an important mediator of apoptosis, recapitulated several phases of a wound healing response in the mouse. The epidermal hyperplasia in the caspase-8 null skin is the culmination of signals exchanged between epidermal keratinocytes, dermal fibroblasts, and leukocytic cells. This reciprocal interaction is initiated by the paracrine signaling of interleukin 1-alpha (IL1-alpha; 147760), which activates both skin stem cell proliferation and cutaneous inflammation. The noncanonical secretion of IL1-alpha is induced by a p38-MAPK (600289)-mediated upregulation of NALP3 (606416), leading to inflammasome assembly and caspase-1 activation. Notably, the increased proliferation of basal keratinocytes is counterbalanced by the growth arrest of suprabasal keratinocytes in the stratified epidermis by IL1-alpha-dependent NF-kappa-B (see 164011) signaling. Lee et al. (2009) concluded that their findings illustrated how the loss of caspase-8 can affect more than programmed cell death to alter the local microenvironment and elicit processes common to wound repair and many neoplastic skin disorders.
In 2 affected sibs from a consanguineous family with caspase-8 deficiency (607271), Chun et al. (2002) identified a homozygous C-to-T transition in the CASP8 gene, resulting in an arg248-to-trp (R248W) substitution within the p18 protease subunit of the protein. The asymptomatic mother, father, and sister were heterozygous carriers of the mutation. In 13 extended family members, Chun et al. (2002) identified 7 asymptomatic heterozygous carriers but found no additional homozygous or immunodeficient individuals.
In 9 unrelated patients with hepatocellular carcinoma (114550) and HBV infection, Soung et al. (2005) identified the same somatic mutation, a 2-bp deletion (1225_1226delTG) in exon 7 that was predicted to result in frameshift and premature termination of amino acid synthesis in the p10 protease subunit.
MacPherson et al. (2004) and Frank et al. (2005) found evidence that the presence of a single-nucleotide polymorphism (SNP) in the CASP8 gene resulting in an asp302-to-his (D302H) substitution (rs1045485) could reduce susceptibility to breast cancer (114480) in British and German cohorts, respectively. Cox et al. (2007) found evidence for a protective effect of the D302H polymorphism in an allele dose-dependent manner in 16,423 cases and 17,109 controls from 14 studies that contributed data to the Breast Cancer Association Consortium (BCAC). The study achieved odds ratios of 0.89 and 0.74 for heterozygotes and rare homozygotes, respectively, compared with common homozygotes. This site was not found to be polymorphic in Korean, Han Chinese, or Japanese women. Cox et al. (2007) noted that the functional consequences of the aspartic acid-to-histidine substitution were not known, and further experiments were required to establish whether D302H itself or another variant in strong linkage disequilibrium with it is causative.
Sun et al. (2007) identified a 6-nucleotide insertion/deletion polymorphism in the CASP8 promoter, -652 AGTAAG ins/del (rs3834129), the deletion variant of which was associated with decreased risk of developing lung cancer (211980) in a population of Han Chinese subjects. The -652 6N deletion was also associated with decreased risk of cancer of various other forms including esophageal, gastric, colorectal, cervical, and breast, acting in an allele dose-dependent manner. The frequency of the -652 6N deletion was significantly lower in individuals with lung cancer (P = 4.1 x 10(-5)).
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