54269 bases with 11 exons.

There are 6 transcriptional variants of CASP8 and they are described in Table 1.

Caspases are a family of cysteinyl aspartate specific proteases which are synthesized as zymogens. Caspase-8 was discovered as a component of the CD95 (Fas/APO-1) death-inducing signaling complex (DISC) (Muzio et al., 1996).

Caspase-8 has a number of isoforms, including procaspase-8a (496 aa), procaspase-8b (479 aa), procaspase-8c (464 aa), procaspase-8e (235 aa), procaspase-8g or caspase-8L (538 aa) and caspase-8 short (108 aa).
Only two isoforms are predominantly expressed in many different tissues and cell lines: procaspase-8a and procaspase-8b (Scaffidi et al., 1997). They act as the main initiator caspases in death receptor-induced apoptosis.
Caspase-8L was reported to be expressed in human peripheral blood lymphocytes as a truncated protein, which lacks the C-terminal protease domain (Horiuchi et al., 2000). Therefore, it is suggested that caspase-8L is recruited into the DISC but remains proteolytically inert, interfering with the transduction of the signal from the DISC (Himeji et al., 2002).
An isoform that is detected in bone marrow mononuclear cells is named caspase-8 short. Although it only contains the first DED and a part of the second DED, overexpression of caspase-8 short is reported to increase sensitivity to apoptosis (Xu et al., 2009).
In addition to caspase-8 isoforms, there is a number of cleavage products described, which are formed in the course of apoptosis. Apoptotic processing of procaspase-8a/b involves generation of the cleavage products p43/p41, p30, the prodomains p26/p24, p18 and p10 (Hoffmann et al., 2009). The latter two cleavage products form the active caspase-8 heterotetramer p102-p182 that triggers apoptosis (Lavrik and Krammer, 2012).

Caspase-8 is expressed in almost all kind of tissues, with the highest expression in the immune system and lowest in the nervous system (McCall et al., 2011).

Procaspase-8 mainly localizes to the cytosol, in close proximity to the membrane (Medema et al., 1997). It may also localize to mitochondria (Qin et al., 2001, Chandra et al., 2004) or centrosomes (Mielgo et al., 2009). Caspase-8 cleavage products are reported to localize to the nucleus as well as the cytosol (Benchoua et al., 2002, Yao et al., 2007).

Caspase-8 is the main initiator caspase in death receptor-induced apoptosis. Upon stimulation, procaspase-8 is recruited to the CD95 or TRAIL DISC, or TNF complex II. Procaspase-8 activation involves dimerization, oligomerization and cleavage (Schleich et al., 2012). The cleavage of procaspase-8 involves several steps, leading to the generation of the active caspase-8 heterotetramer p102-p182 (Lavrik and Krammer, 2012). Depending on the cell type, active caspase-8 either directly cleaves effector caspases (caspase-3 and caspase-7) or cleaves Bid, which eventually leads to release of cytochrome C and apoptosome formation followed by cleavage of effector caspase-3, caspase-6 and caspase-7 by procaspase-9 (Scaffidi et al., 1998; Scaffidi et al., 1999).
In addition to apoptosis, caspase-8 has a role in programmed necrosis (necroptosis) as well. Caspase-8 can be recruited to the necroptotic complexes (necrosome or ripoptosome) together with RIP1, RIP3 and FADD. It would then cleave RIP1 and RIP3, and therefore block necroptosis (Stupack et al., 2006, Feoktistova et al., 2011; Tenev et al., 2011).
Caspase-8 also has an essential role for NF-kB signaling via many different stimuli including CD95, TRAIL, TCR and TLR stimulations (Kataoka and Tschopp, 2004; Dohrman et al., 2005; Su et al., 2005; Lemmers et al., 2007; Grunert et al., 2012). Interestingly, although the activation of procaspase-8 to p102-p182 heterotetramer is necessary for MAPK signaling (Kober et al., 2011), it is not necessary for NF-kB signaling upon CD95 stimulation (Neumann et al., 2010).
Caspase-8 has been also reported to affect metastasis. Interestingly, although loss of caspase-8 potentiates metastasis, under conditions where apoptosis is compromised, caspase-8 can promote tumor cell migration and metastasis (Stupack et al., 2006, Barbero et al., 2009).

Caspase-10, FADD, c-FLIP.

A homozygous C to T mutation at residue 248 leads to familial autoimmune lymphoproliferative syndrome type 2B.

Various somatic mutations of CASP8 are identified in different carcinomas. Mutations are observed at different parts of caspase-8, but they all lead to a catalytically inactive form.
- Hepatocellular carcinoma: CASP8 is frequently inactivated by the frameshift somatic mutation 1225-1226delTG in hepatocellular carcinomas, resulting in a premature termination of amino-acid synthesis in the p10 protease subunit (Soung et al., 2005b).
- Gastric carcinoma: Inactivating CASP8 mutations are detected at different sites in about 10% of advanced gastric carcinomas (Soung et al., 2005a).
- Colorectal carcinoma: Inactivating CASP8 mutations are detected at different sites in about 5% of invasive colorectal carcinomas (Kim et al., 2003).
- Vulvar squamous carcinoma: Deletion of leucine 62 (ΔLeu62casp-8) is detected in A431 human vulvar squamous carcinoma cells. ΔLeu62casp-8 has a shorter half-life than wild-type caspase-8 and cannot interact with caspase-8 or FADD; therefore lost its proapoptotic activity (Liu et al., 2002).
- Head and neck carcinoma: A mutation was detected in the tumor cells from head and neck carcinoma that modifies the stop codon and lengthening the protein by 88 amino acids (Mandruzzato et al., 1997).
- Neuroblastoma : An Alanine to Valine missense mutation was detected at codon 96 in a neuroblastoma sample which lacks CASP8 mRNA expression (Takita et al., 2001).