CASP8

GeneName

CASP8

Summary

CASP8, also known as caspase 8 or FLICE, is a 55 kDa cysteine protease that plays a pivotal role in the apoptotic process. It is predominantly expressed in the cytoplasm and nucleus, and is involved in the extrinsic apoptotic signaling pathway, particularly through its interactions with death receptors. CASP8 functions as a key initiator of apoptosis, activating downstream caspases and facilitating the execution phase of cell death. It is also implicated in various biological processes such as angiogenesis, B cell activation, and macrophage differentiation. Additionally, CASP8 has roles in regulating inflammatory responses and cytokine production, highlighting its importance in both cell survival and death mechanisms.

Importance

CASP8 is relevant to: - Cancer research due to its role in apoptosis and potential as a therapeutic target in tumourigenesis - Immune responses, particularly in the activation of natural killer cells and T cells, influencing adaptive immunity - Neurodegenerative diseases where dysregulation of apoptosis contributes to neuronal loss - Inflammatory conditions, as it is involved in the pyroptotic inflammatory response and cytokine regulation - Cardiovascular development, given its involvement in heart development and associated signalling pathways

Top Products

For researchers investigating CASP8, we recommend two excellent primary antibodies. The first is the well-cited polyclonal antibody, Anti-Caspase-8 antibody (ab25901), which has garnered 169 citations, highlighting its reliability in the field. This antibody is suitable for a variety of applications, including Western blotting (WB), immunohistochemistry (IHC), and immunocytochemistry (ICC). Additionally, we offer the recombinant antibody, Anti-Pro Caspase-8 antibody [EPR162] (ab108333), which has been validated in knockout models and is ideal for WB and IHC applications. With 50 citations, this monoclonal antibody provides batch-to-batch consistency, making it a dependable choice for researchers seeking precise CASP8 detection. The Caspase-8 (active) FITC Staining Kit (ab65614), supported by 6 citations, is an excellent option for researchers looking to accurately assess active Caspase-8 in their experiments.

Abcam Product Citation Summary

The data indicates that CASP8 is a significant target in various studies related to apoptosis, mitochondrial damage, and necroptosis across different species, including mouse and human. The use of multiple antibodies in diverse cell types highlights the importance of CASP8 in understanding cellular processes in health and disease.

Abcam Product Citation Table

Domain

The catalytic domain is sufficient for recruitment to lamellipodia but catalytic activity is not necessary.

Isoform 9

Contains a N-terminal extension that is required for interaction with the BCAP31 complex.

Function

Thiol protease that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood (PubMed:23516580, PubMed:35338844, PubMed:35446120, PubMed:8681376, PubMed:8681377, PubMed:8962078, PubMed:9006941, PubMed:9184224). Initiator protease that induces extrinsic apoptosis by mediating cleavage and activation of effector caspases responsible for FAS/CD95-mediated and TNFRSF1A-induced cell death (PubMed:23516580, PubMed:35338844, PubMed:35446120, PubMed:8681376, PubMed:8681377, PubMed:8962078, PubMed:9006941, PubMed:9184224). Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10 (PubMed:16916640, PubMed:8962078, PubMed:9006941). Binding to the adapter molecule FADD recruits it to either receptor FAS/TNFRSF6 or TNFRSF1A (PubMed:8681376, PubMed:8681377). The resulting aggregate called the death-inducing signaling complex (DISC) performs CASP8 proteolytic activation (PubMed:9184224). The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases (PubMed:9184224). Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC (PubMed:9184224). Also cleaves and activates BID, thereby promoting cytochrome C release from mitochrondria (By similarity). In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at 'Asp-324', which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response (PubMed:31827280, PubMed:31827281). Also able to initiate pyroptosis by mediating cleavage and activation of gasdermin-C and -D (GSDMC and GSDMD, respectively): gasdermin cleavage promotes release of the N-terminal moiety that binds to membranes and forms pores, triggering pyroptosis (PubMed:32929201, PubMed:34012073). Initiates pyroptosis following inactivation of MAP3K7/TAK1 (By similarity). Also acts as a regulator of innate immunity by mediating cleavage and inactivation of N4BP1 downstream of TLR3 or TLR4, thereby promoting cytokine production (By similarity). May participate in the Granzyme B (GZMB) cell death pathways (PubMed:8755496). Cleaves PARP1 and PARP2 (PubMed:8681376). Independent of its protease activity, promotes cell migration following phosphorylation at Tyr-380 (PubMed:18216014, PubMed:27109099).

Isoform 5

Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.

Isoform 6

Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.

Isoform 7

Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex (Probable). Acts as an inhibitor of the caspase cascade (PubMed:12010809).

Isoform 8

Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.

Involvement in disease

Caspase-8 deficiency

CASP8D

Disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

Generation of the p10 and p18 subunits requires association with the death-inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease. GZMB and CASP10 can be involved in these processing events.

Phosphorylation on Ser-387 during mitosis by CDK1 inhibits activation by proteolysis and prevents apoptosis (PubMed:20937773). Phosphorylation on Tyr-380 by SRC is mediated by interaction with the SRC SH2 domain and does not affect dimerization or recruitment to the death-inducing signaling complex (DISC) but negatively regulates DISC-mediated processing and activation of CASP8, down-regulating its proapoptotic function (PubMed:16619028, PubMed:27109099). Phosphorylation on Tyr-380 also enhances localization to lamellipodia in migrating cells (PubMed:18216014).

(Microbial infection) ADP-riboxanation by C.violaceum CopC blocks CASP8 processing, preventing CASP8 activation and ability to mediate extrinsic apoptosis.

(Microbial infection) Proteolytically cleaved by the cowpox virus CRMA death inhibitory protein.

Sequence Similarities

Belongs to the peptidase C14A family.

Tissue Specificity

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.

Cellular localization

• Cytoplasm
• Nucleus
• Cell projection
• Lamellipodium
• Recruitment to lamellipodia of migrating cells is enhanced by phosphorylation at Tyr-380.

Alternative names

MCH5, CASP8, Caspase-8, CASP-8, Apoptotic cysteine protease, Apoptotic protease Mch-5, CAP4, FADD-homologous ICE/ced-3-like protease, FADD-like ICE, ICE-like apoptotic protease 5, MORT1-associated ced-3 homolog, FLICE, MACH

Database links

swissprot:Q14790 omim:601763 entrezGene:841

Other research areas

• Immuno-oncology