CASP8 Gene

The CASP8 gene (CASP8 stands for "caspase 8") is a protein-coding gene located on chromosome 2q33.1. Many alternatively spliced transcript variants encoding different isoforms have been described, although full-length sequences have not been determined for all variants. For the isoforms listed below:

• Isoform 5: Lacks the catalytic site and may affect the pro-apoptotic activity of the "death-inducing signaling complex (DISC)".
• Isoform 6: Lacks the catalytic site and may impair the pro-apoptotic activity of the "death-inducing signaling complex (DISC)". CASP8_HUMAN,Q14790
• Isoform 7: Lacks the catalytic site and may impair the pro-apoptotic activity of the "death-inducing signaling complex (DISC)". Acts as an inhibitor of the caspase cascade.
• Isoform 8: Lacks the catalytic site and may impair the pro-apoptotic activity of the death-inducing signaling complex (DISC).

The CASP8 gene encodes a member of the cysteine aspartic acid protease (caspase) family. Caspases (cysteinyl aspartate proteases) are involved in the signaling pathways of apoptosis, necrosis and inflammation. These enzymes can be divided into initiators and effectors. The initiator isoforms are activated by and interact with upstream adaptor molecules.

Caspases exist as inactive proenzymes consisting of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing on conserved internal aspartic acid residues to generate a heterodimeric enzyme consisting of the large and small subunits. This dimeric caspase enzyme is involved in programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with the Fas-interacting protein FADD.

Caspase 8, encoded by the CASP8 gene, is a thiol protease that plays a key role in programmed cell death by acting as a molecular switch for:

• Apoptosis
• Necroptosis
• Pyroptosis

. It is considered an initiator protease that induces extrinsic apoptosis by mediating the cleavage and activation of effector caspases responsible for TNFRSF6/FAS-mediated and TNFRSF1A-induced cell death. (Blasche S et al. 2013).

The encoded CASP8 protein cleaves and activates the effector caspases CASP3, CASP4, CASP6, CASP7, CASP9, and CASP10 . Binding to the adapter molecule FADD recruits it to either the receptor TNFRSF6/FAS or TNFRSF1A (Medema JP et al 1997). The resulting aggregate, termed thedeath-inducing signaling complex (DISC), carries out proteolytic activation of CASP8. The active dimeric enzyme is then released from the DISC and is free to activate downstream apoptotic proteases. In addition to extrinsic apoptosis, it also acts as a negative regulator of necroptosis: it cleaves RIPK1 at Asp-324, which is critical for inhibiting RIPK1 kinase activity and limits TNF-induced apoptosis, necroptosis, and inflammatory response (Tao P et al. 2020). May also induce pyroptosis by mediating the cleavage and activation of gasdermin-D (GSDMD): GSDMD cleavage promotes the release of the N-terminal component (gasdermin-D, N-terminal), which binds to membranes and forms pores, inducing pyroptosis.

Diseases associated with CASP8 include autoimmune lymphoproliferative syndrome type 2b (caspase 8 deficiency) and hepatocellular carcinoma.

1. Blasche S et al. (2013) The E. coli effector protein NleF is a caspase inhibitor. PLoS One 8: e58937.
2. Chun HJ et al (2002) Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419: 395-399.
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4. Medema JP et al (1997) FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J 16: 2794-2804.
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6. Tao P et al (2020) A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1. Nature 577(7788):109-114.
7. Teachey DT et al (2009) Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS). Brit J Haemat 148: 205-216.
8. Wu Y et al. (2016) Caspase-8 and Caspase-9 Functioned Differently at Different Stages of the Cyclic Stretch-Induced Apoptosis in Human Periodontal Ligament Cells. PLoS One 11: e0168268.